Compounds and Methods for Reducing LRRK2 Expression

ABSTRACT

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of LRRK2 RNA in a cell or animal, and in certain instances reducing the amount of LRRK2 protein in a cell or animal. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a neurodegenerative disease. Such symptoms and hallmarks include ataxia, neuropathy, and aggregate formation. Such neurodegenerative diseases include Parkinson&#39;s disease.

SEQUENCE LISTING

The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled BIOL0324USASEQ_ST25.txt, created on Dec. 2, 2020, which is 1.12 MB in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.

FIELD

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of leucine-rich repeat kinase 2 (LRRK2) RNA in a cell or animal, and in certain instances reducing the amount of LRRK2 protein in a cell or animal. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a neurodegenerative disease. Such symptoms and hallmarks include ataxia, neuropathy, and aggregate formation. Such neurodegenerative diseases include Parkinson's disease.

BACKGROUND

The LRRK2 gene encodes a protein with an armadillo repeat (ARM) region, an ankyrin repeat (ANK) region, a leucine-rich repeat (LRR) domain, a kinase domain, a RAS domain, a GTPase domain, and a WD40 domain. The protein is present largely in the cytoplasm but also associates with the mitochondrial outer membrane. One segment of the LRRK2 protein is enriched with leucine and may be involved in signal transduction and cytoskeleton assembly. Other parts of the LRRK2 protein are also thought to be involved in protein-protein interactions. Additional studies indicate that LRRK2 protein has an enzyme function known as kinase activity, including phosphorylation and GTPase activity. LRRK2 is active in the brain and other tissues throughout the body.

Genomewide association studies have found an association between LRRK2 and Parkinson's disease. Indeed, LRRK2 is the greatest known genetic contributor to Parkinson's disease. Nonetheless, Parkinson's disease has not been considered to be a genetic disease. The majority of Parkinson's disease cases are idiopathic. Approximately 10 percent of Parkinson's disease cases have been linked to a genetic cause. Mutations in the LRRK2 gene are the most common cause of Parkinson's disease in this relatively small group, representing one to two percent of total Parkinson's disease cases.

Currently there is a lack of acceptable options for treating neurodegenerative diseases such as Parkinson's disease, including non-LRRK2 mediated Parkinson's disease. It is therefore an object herein to provide compounds, methods, and pharmaceutical compositions for the treatment of such diseases.

SUMMARY OF THE INVENTION

Provided herein are compounds, methods and pharmaceutical compositions for reducing the amount or activity of LRRK2 RNA, and in certain embodiments reducing the amount of LRRK2 protein in a cell or animal. In certain embodiments, the animal has a neurodegenerative disease. In certain embodiments, the animal has Parkinson's disease. In certain embodiments, compounds useful for reducing expression of LRRK2 RNA are oligomeric compounds. In certain embodiments, compounds useful for reducing expression of LRRK2 RNA are modified oligonucleotides.

Also provided are methods useful for ameliorating at least one symptom or hallmark of a neurodegenerative disease. In certain embodiments, the neurodegenerative disease is Parkinson's disease. In certain embodiments, the Parkinson's disease is either LRRK2 mediated Parkinson's disease or non-LRRK2 mediated Parkinson's disease. In certain embodiments, the symptom or hallmark includes ataxia, neuropathy, and aggregate formation. In certain embodiments, amelioration of these symptoms results in improved motor function, reduced neuropathy, and reduction in number of aggregates.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive. Herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the use of “or” means “and/or” unless stated otherwise. Furthermore, the use of the term “including” as well as other forms, such as “includes” and “included”, is not limiting. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit, unless specifically stated otherwise.

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, and treatises, are hereby expressly incorporated-by-reference for the portions of the document discussed herein, as well as in their entirety.

Definitions

Unless specific definitions are provided, the nomenclature used in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art. Where permitted, all patents, applications, published applications and other publications and other data referred to throughout in the disclosure are incorporated by reference herein in their entirety.

Unless otherwise indicated, the following terms have the following meanings:

Definitions

As used herein, “2′-deoxynucleoside” means a nucleoside comprising a 2′-H(H) deoxyribosyl sugar moiety, as found in naturally occurring deoxyribonucleic acids (DNA). In certain embodiments, a 2′-deoxynucleoside may comprise a modified nucleobase or may comprise an RNA nucleobase (uracil).

As used herein, “2′-substituted nucleoside” means a nucleoside comprising a 2′-substituted sugar moiety. As used herein, “2′-substituted” in reference to a sugar moiety means a sugar moiety comprising at least one 2′-substituent group other than H or OH.

As used herein, “5-methyl cytosine” means a cytosine modified with a methyl group attached to the 5 position. A 5-methyl cytosine is a modified nucleobase.

As used herein, “administering” means providing a pharmaceutical agent to an animal.

As used herein, “animal” means a human or non-human animal.

As used herein, “antisense activity” means any detectable and/or measurable change attributable to the hybridization of an antisense compound to its target nucleic acid. In certain embodiments, antisense activity is a decrease in the amount or expression of a target nucleic acid or protein encoded by such target nucleic acid compared to target nucleic acid levels or target protein levels in the absence of the antisense compound.

As used herein, “antisense compound” means an oligomeric compound capable of achieving at least one antisense activity.

As used herein, “ameliorate” in reference to a treatment means improvement in at least one symptom relative to the same symptom in the absence of the treatment. In certain embodiments, amelioration is the reduction in the severity or frequency of a symptom or the delayed onset or slowing of progression in the severity or frequency of a symptom. In certain embodiments, the symptom or hallmark is ataxia, neuropathy, and aggregate formation. In certain embodiments, amelioration of these symptoms results in improved motor function, reduced neuropathy, and reduction in number of aggregates.

As used herein, “bicyclic nucleoside” or “BNA” means a nucleoside comprising a bicyclic sugar moiety.

As used herein, “bicyclic sugar” or “bicyclic sugar moiety” means a modified sugar moiety comprising two rings, wherein the second ring is formed via a bridge connecting two of the atoms in the first ring thereby forming a bicyclic structure. In certain embodiments, the first ring of the bicyclic sugar moiety is a furanosyl moiety. In certain embodiments, the bicyclic sugar moiety does not comprise a furanosyl moiety.

As used herein, “cleavable moiety” means a bond or group of atoms that is cleaved under physiological conditions, for example, inside a cell, an animal, or a human.

As used herein, “complementary” in reference to an oligonucleotide means that at least 70% of the nucleobases of the oligonucleotide or one or more regions thereof and the nucleobases of another nucleic acid or one or more regions thereof are capable of hydrogen bonding with one another when the nucleobase sequence of the oligonucleotide and the other nucleic acid are aligned in opposing directions. Complementary nucleobases means nucleobases that are capable of forming hydrogen bonds with one another. Complementary nucleobase pairs include adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine (C) and guanine (G), 5-methyl cytosine (mC) and guanine (G). Complementary oligonucleotides and/or nucleic acids need not have nucleobase complementarity at each nucleoside. Rather, some mismatches are tolerated. As used herein, “fully complementary” or “100% complementary” in reference to oligonucleotides means that oligonucleotides are complementary to another oligonucleotide or nucleic acid at each nucleoside of the oligonucleotide.

As used herein, “conjugate group” means a group of atoms that is directly attached to an oligonucleotide. Conjugate groups include a conjugate moiety and a conjugate linker that attaches the conjugate moiety to the oligonucleotide.

As used herein, “conjugate linker” means a single bond or a group of atoms comprising at least one bond that connects a conjugate moiety to an oligonucleotide.

As used herein, “conjugate moiety” means a group of atoms that is attached to an oligonucleotide via a conjugate linker.

As used herein, “contiguous” in the context of an oligonucleotide refers to nucleosides, nucleobases, sugar moieties, or internucleoside linkages that are immediately adjacent to each other. For example, “contiguous nucleobases” means nucleobases that are immediately adjacent to each other in a sequence.

As used herein, “constrained ethyl” or “cEt” or “cEt modified sugar” means a β-D ribosyl bicyclic sugar moiety wherein the second ring of the bicyclic sugar is formed via a bridge connecting the 4′-carbon and the 2′-carbon of the β-D ribosyl sugar moiety, wherein the bridge has the formula 4′-CH(CH₃)—O-2′, and wherein the methyl group of the bridge is in the S configuration.

As used herein, “cEt nucleoside” means a nucleoside comprising cEt modified sugar.

As used herein, “chirally enriched population” means a plurality of molecules of identical molecular formula, wherein the number or percentage of molecules within the population that contain a particular stereochemical configuration at a particular chiral center is greater than the number or percentage of molecules expected to contain the same particular stereochemical configuration at the same particular chiral center within the population if the particular chiral center were stereorandom. Chirally enriched populations of molecules having multiple chiral centers within each molecule may contain one or more stereorandom chiral centers. In certain embodiments, the molecules are modified oligonucleotides. In certain embodiments, the molecules are compounds comprising modified oligonucleotides.

As used herein, “gapmer” means a modified oligonucleotide comprising an internal region having a plurality of nucleosides that support RNase H cleavage positioned between external regions having one or more nucleosides, wherein the nucleosides comprising the internal region are chemically distinct from the nucleoside or nucleosides comprising the external regions. The internal region may be referred to as the “gap” and the external regions may be referred to as the “wings.” Unless otherwise indicated, “gapmer” refers to a sugar motif. Unless otherwise indicated, the sugar moieties of the nucleosides of the gap of a gapmer are unmodified 2′-deoxyribosyl. Thus, the term “MOE gapmer” indicates a gapmer having a sugar motif of 2′-MOE nucleosides in both wings and a gap of 2′-deoxynucleosides. Unless otherwise indicated, a MOE gapmer may comprise one or more modified internucleoside linkages and/or modified nucleobases and such modifications do not necessarily follow the gapmer pattern of the sugar modifications.

As used herein, “hotspot region” is a range of nucleobases on a target nucleic acid amenable to oligomeric compound-mediated reduction of the amount or activity of the target nucleic acid.

As used herein, “hybridization” means the pairing or annealing of complementary oligonucleotides and/or nucleic acids. While not limited to a particular mechanism, the most common mechanism of hybridization involves hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases.

As used herein, the term “internucleoside linkage” is the covalent linkage between adjacent nucleosides in an oligonucleotide. As used herein “modified internucleoside linkage” means any internucleoside linkage other than a phosphodiester internucleoside linkage. “Phosphorothioate internucleoside linkage” is a modified internucleoside linkage in which one of the non-bridging oxygen atoms of a phosphodiester internucleoside linkage is replaced with a sulfur atom.

As used herein, “linker-nucleoside” means a nucleoside that links, either directly or indirectly, an oligonucleotide to a conjugate moiety. Linker-nucleosides are located within the conjugate linker of an oligomeric compound. Linker-nucleosides are not considered part of the oligonucleotide portion of an oligomeric compound even if they are contiguous with the oligonucleotide.

As used herein, “non-bicyclic modified sugar moiety” means a modified sugar moiety that comprises a modification, such as a substituent, that does not form a bridge between two atoms of the sugar to form a second ring.

As used herein, “mismatch” or “non-complementary” means a nucleobase of a first oligonucleotide that is not complementary with the corresponding nucleobase of a second oligonucleotide or target nucleic acid when the first and second oligonucleotide are aligned.

As used herein, “MOE” means methoxyethyl. “2′-MOE” or “2′-MOE modified sugar” means a 2′-OCH₂CH₂OCH₃ group in place of the 2′-OH group of a ribosyl sugar moiety. As used herein, “2′-MOE nucleoside” means a nucleoside comprising a 2′-MOE modified sugar.

As used herein, “motif” means the pattern of unmodified and/or modified sugar moieties, nucleobases, and/or internucleoside linkages, in an oligonucleotide.

As used herein, “RNA” means an RNA transcript that encodes a protein and includes pre-mRNA and mature mRNA unless otherwise specified.

As used herein, “neurodegenerative disease” means a condition marked by progressive loss of function or structure, including loss of motor function and death of neurons. In certain embodiments, the neurodegenerative disease is Parkinson's disease. In certain embodiments, the Parkinson's disease may be LRRK2 mediated Parkinson's disease or non-LRRK2 mediated Parkinson's disease.

“Non-LRRK2 mediated Parkinson's Disease” is a diagnosis of Parkinson's disease not associated with a causative LRRK2 genetic mutation. Causative LRRK2 genetic mutations include G2019S, R1441C, R1441G, 12020T, and Y1699C. Diagnosis of Parkinson's disease may be accomplished by any method including evaluating an individual's medical history, observation of signs and symptoms, and standard clinical tests or assessments. Genetic testing for a mutation associated with LRRK2, such as G2019S, R1441C, R1441G, 12020T, and Y1699C, may reveal whether an individual has non-LRRK2 mediated Parkinson's disease. An individual having a diagnosis of Parkinson's disease, but without a causative LRRK2 mutation, has non-LRRK2 mediated Parkinson's disease. “Identifying an animal having non-LRRK2 mediated Parkinson's Disease” means identifying an animal having been diagnosed with Parkinson's Disease or predisposed to develop Parkinson's Disease without a causative LRRK2 mutation.

As used herein, “nucleobase” means an unmodified nucleobase or a modified nucleobase. As used herein an “unmodified nucleobase” is adenine (A), thymine (T), cytosine (C), uracil (U), or guanine (G). As used herein, a “modified nucleobase” is a group of atoms other than unmodified A, T, C, U, or G capable of pairing with at least one unmodified nucleobase. A “5-methyl cytosine” is a modified nucleobase. A universal base is a modified nucleobase that can pair with any one of the five unmodified nucleobases. As used herein, “nucleobase sequence” means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkage modification.

As used herein, “nucleoside” means a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each, independently, unmodified or modified. As used herein, “modified nucleoside” means a nucleoside comprising a modified nucleobase and/or a modified sugar moiety. Modified nucleosides include abasic nucleosides, which lack a nucleobase. “Linked nucleosides” are nucleosides that are connected in a contiguous sequence (i.e., no additional nucleosides are presented between those that are linked).

As used herein, “oligomeric compound” means an oligonucleotide and optionally one or more additional features, such as a conjugate group or terminal group. An oligomeric compound may be paired with a second oligomeric compound that is complementary to the first oligomeric compound or may be unpaired. A “singled-stranded oligomeric compound” is an unpaired oligomeric compound. The term “oligomeric duplex” means a duplex formed by two oligomeric compounds having complementary nucleobase sequences. Each oligomeric compound of an oligomeric duplex may be referred to as a “duplexed oligomeric compound.”

As used herein, “oligonucleotide” means a strand of linked nucleosides connected via internucleoside linkages, wherein each nucleoside and internucleoside linkage may be modified or unmodified. Unless otherwise indicated, oligonucleotides consist of 8-50 linked nucleosides. As used herein, “modified oligonucleotide” means an oligonucleotide, wherein at least one nucleoside or internucleoside linkage is modified. As used herein, “unmodified oligonucleotide” means an oligonucleotide that does not comprise any nucleoside modifications or internucleoside modifications.

As used herein, “pharmaceutically acceptable carrier or diluent” means any substance suitable for use in administering to an animal Certain such carriers enable pharmaceutical compositions to be formulated as, for example, tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspension and lozenges for the oral ingestion by a subject. In certain embodiments, a pharmaceutically acceptable carrier or diluent is sterile water, sterile saline, sterile buffer solution or sterile artificial cerebrospinal fluid.

As used herein “pharmaceutically acceptable salts” means physiologically and pharmaceutically acceptable salts of compounds. Pharmaceutically acceptable salts retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto.

As used herein “pharmaceutical composition” means a mixture of substances suitable for administering to a subject. For example, a pharmaceutical composition may comprise an oligomeric compound and a sterile aqueous solution. In certain embodiments, a pharmaceutical composition shows activity in free uptake assay in certain cell lines.

As used herein “prodrug” means a therapeutic agent in a form outside the body that is converted to a different form within an animal or cells thereof. Typically conversion of a prodrug within the animal is facilitated by the action of an enzymes (e.g., endogenous or viral enzyme) or chemicals present in cells or tissues and/or by physiologic conditions.

As used herein, “reducing or inhibiting the amount or activity” refers to a reduction or blockade of the transcriptional expression or activity relative to the transcriptional expression or activity in an untreated or control sample and does not necessarily indicate a total elimination of transcriptional expression or activity.

As used herein, “RNAi compound” means an antisense compound that acts, at least in part, through RISC or Ago2 to modulate a target nucleic acid and/or protein encoded by a target nucleic acid. RNAi compounds include, but are not limited to double-stranded siRNA, single-stranded RNA (ssRNA), and microRNA, including microRNA mimics In certain embodiments, an RNAi compound modulates the amount, activity, and/or splicing of a target nucleic acid. The term RNAi compound excludes antisense compounds that act through RNase H.

As used herein, “self-complementary” in reference to an oligonucleotide means an oligonucleotide that at least partially hybridizes to itself.

As used herein, “siRNA” refers to a ribonucleic acid molecule having a duplex structure including two anti-parallel and substantially complementary nucleic acid strands. The two strands forming the duplex structure may be different portions of one larger RNA molecule, or they may be separate RNA molecules. Where the two strands are part of one larger molecule, and therefore are connected by consecutive nucleobases between the 3′-end of one strand and the 5′ end of the respective other strand forming the duplex structure, the connecting RNA chain is referred to as a “hairpin loop”. The RNA strands may have the same or a different number of nucleotides.

As used herein, “standard cell assay” means the assay described in Example 4 and reasonable variations thereof.

As used herein, “standard in vivo assay’ means the experiment described in Example 14 and reasonable variations thereof.

As used herein, “stereorandom chiral center” in the context of a population of molecules of identical molecular formula means a chiral center having a random stereochemical configuration. For example, in a population of molecules comprising a stereorandom chiral center, the number of molecules having the (S) configuration of the stereorandom chiral center may be but is not necessarily the same as the number of molecules having the (R) configuration of the stereorandom chiral center. The stereochemical configuration of a chiral center is considered random when it is the results of a synthetic method that is not designed to control the stereochemical configuration. In certain embodiments, a stereorandom chiral center is a stereorandom phosphorothioate internucleoside linkage.

As used herein, “sugar moiety” means an unmodified sugar moiety or a modified sugar moiety. As used herein, “unmodified sugar moiety” means a 2′-OH(H) ribosyl moiety, as found in RNA (an “unmodified RNA sugar moiety”), or a 2′-H(H) deoxyribosyl moiety, as found in DNA (an “unmodified DNA sugar moiety”). Unmodified sugar moieties have one hydrogen at each of the 1′, 3′, and 4′ positions, an oxygen at the 3′ position, and two hydrogens at the 5′ position. As used herein, “modified sugar moiety” or “modified sugar” means a modified furanosyl sugar moiety or a sugar surrogate.

As used herein, “sugar surrogate” means a modified sugar moiety having other than a furanosyl moiety that can link a nucleobase to another group, such as an internucleoside linkage, conjugate group, or terminal group in an oligonucleotide. Modified nucleosides comprising sugar surrogates can be incorporated into one or more positions within an oligonucleotide and such oligonucleotides are capable of hybridizing to complementary oligomeric compounds or target nucleic acids.

As used herein, “target nucleic acid” and “target RNA” mean a nucleic acid that an antisense compound is designed to affect.

As used herein, “target region” means a portion of a target nucleic acid to which an oligomeric compound is designed to hybridize.

As used herein, “terminal group” means a chemical group or group of atoms that is covalently linked to a terminus of an oligonucleotide.

As used herein, “therapeutically effective amount” means an amount of a pharmaceutical agent that provides a therapeutic benefit to an animal. For example, a therapeutically effective amount improves a symptom of a disease.

Certain Embodiments

The present disclosure provides the following non-limiting numbered embodiments:

Embodiment 1. An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to an equal length portion of a LRRK2 nucleic acid, and wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar, a sugar surrogate, and a modified internucleoside linkage.

Embodiment 2: An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides and having a nucleobase sequence comprising at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOS: 30-3847.

Embodiment 3: An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides and having a nucleobase sequence comprising a portion of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 contiguous nucleobases, wherein the portion is complementary to:

an equal length portion of nucleobases 18,633-18,658 of SEQ ID NO: 2;

an equal length portion of nucleobases 21,721-21,755 of SEQ ID NO: 2;

an equal length portion of nucleobases 27,963-28,016 of SEQ ID NO: 2;

an equal length portion of nucleobases 35,415-35,446 of SEQ ID NO: 2;

an equal length portion of nucleobases 77,221-77,264 of SEQ ID NO: 2;

an equal length portion of nucleobases 81,581-81,612 and/or 87,838-87,869 of SEQ ID NO: 2;

an equal length portion of nucleobases 81,627-81,651 of SEQ ID NO: 2;

an equal length portion of nucleobases 82,058-82,081 of SEQ ID NO: 2;

an equal length portion of nucleobases 82,180-82,220 of SEQ ID NO: 2;

an equal length portion of nucleobases 82,500-82,525 of SEQ ID NO: 2;

an equal length portion of nucleobases 91,038-91,067 of SEQ ID NO: 2;

an equal length portion of nucleobases 92,148-92,173 of SEQ ID NO: 2;

am equal length portion of nucleobases 98,186-98,220 of SEQ ID NO: 2;

an equal length portion of nucleobases 98,218-98,242 of SEQ ID NO: 2;

an equal length portion of nucleobases 99,199-99,223 of SEQ ID NO: 2;

an equal length portion of nucleobases 119,903-119,936 of SEQ ID NO: 2; or an equal length portion of nucleobases 4,062-4,086 of SEQ ID NO: 1.

Embodiment 4. The oligomeric compound of any of embodiments 1-3, wherein the modified oligonucleotide has a nucleobase sequence that is at least 80%, 85%, 90%, 95%, or 100% complementary to the nucleobase sequence of SEQ ID NO: 1 or SEQ ID NO: 2, when measured across the entire nucleobase sequence of the modified oligonucleotide.

Embodiment 5. The oligomeric compound of any of embodiments 1-4, wherein the modified oligonucleotide comprises at least one modified nucleoside.

Embodiment 6. The oligomeric compound of embodiment 5, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a modified sugar moiety.

Embodiment 7. The oligomeric compound of embodiment 6, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety.

Embodiment 8. The oligomeric compound of embodiment 7, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety having a 2′-4′ bridge, wherein the 2′-4′ bridge is selected from —O—CH₂—; and —O—CH(CH₃)—.

Embodiment 9. The oligomeric compound of any of embodiments 5-8, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a non-bicyclic modified sugar moiety.

Embodiment 10. The oligomeric compound of embodiment 9, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a non-bicyclic modified sugar moiety comprising a 2′-MOE modified sugar or 2′-OMe modified sugar.

Embodiment 11. The oligomeric compound of any of embodiments 5-10, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a sugar surrogate.

Embodiment 12. The oligomeric compound of embodiment 11, wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a sugar surrogate selected from morpholino and PNA.

Embodiment 13. The oligomeric compound of any of embodiments 1-12, wherein the modified oligonucleotide has a sugar motif comprising:

a 5′-region consisting of 1-5 linked 5′-region nucleosides;

a central region consisting of 6-10 linked central region nucleosides; and

a 3′-region consisting of 1-5 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a modified sugar moiety and each of the central region nucleosides comprises an unmodified 2′-deoxyribosyl sugar moiety.

Embodiment 14. The oligomeric compound of any of embodiments 1-13, wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.

Embodiment 15. The oligomeric compound of embodiment 14, wherein each internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage.

Embodiment 16. The oligomeric compound of embodiment 14 or 15 wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage.

Embodiment 17. The oligomeric compound of embodiment 14 or 16 wherein the modified oligonucleotide comprises at least one phosphodiester internucleoside linkage.

Embodiment 18. The oligomeric compound of any of embodiments 14, 16, or 17, wherein each internucleoside linkage is either a phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage.

Embodiment 19. The oligomeric compound of any of embodiments 1-18, wherein the modified oligonucleotide comprises at least one modified nucleobase.

Embodiment 20. The oligomeric compound of embodiment 19, wherein the modified nucleobase is a 5-methyl cytosine.

Embodiment 21. The oligomeric compound of any of embodiments 1-20, wherein the modified oligonucleotide consists of 12-30, 12-22, 12-20, 14-20, 15-25, 16-20, 18-22 or 18-20 linked nucleosides.

Embodiment 22. The oligomeric compound of any of embodiments 1-21, wherein the modified oligonucleotide consists of 17 or 20 linked nucleosides.

Embodiment 23. The oligomeric compound of any of embodiments 1-22 consisting of the modified oligonucleotide.

Embodiment 24. The oligomeric compound of any of embodiments 1-22 comprising a conjugate group comprising a conjugate moiety and a conjugate linker.

Embodiment 25. The oligomeric compound of embodiment 24, wherein the conjugate group comprises a GalNAc cluster comprising 1-3 GalNAc ligands.

Embodiment 26. The oligomeric compound of embodiment 24 or 25, wherein the conjugate linker consists of a single bond.

Embodiment 27. The oligomeric compound of embodiment 25, wherein the conjugate linker is cleavable.

Embodiment 28. The oligomeric compound of embodiment 27, wherein the conjugate linker comprises 1-3 linker-nucleosides.

Embodiment 29. The oligomeric compound of any of embodiments 24-28, wherein the conjugate group is attached to the modified oligonucleotide at the 5′-end of the modified oligonucleotide.

Embodiment 30. The oligomeric compound of any of embodiments 24-28, wherein the conjugate group is attached to the modified oligonucleotide at the 3′-end of the modified oligonucleotide.

Embodiment 31. The oligomeric compound of any of embodiments 1-30 comprising a terminal group.

Embodiment 32. The oligomeric compound of any of embodiments 1-31 wherein the oligomeric compound is a singled-stranded oligomeric compound.

Embodiment 33. The oligomeric compound of any of embodiments 1-27 or 29-31, wherein the oligomeric compound does not comprise linker-nucleosides.

Embodiment 34. An oligomeric duplex comprising an oligomeric compound of any of embodiments 1-31 or 33.

Embodiment 35. An antisense compound comprising or consisting of an oligomeric compound of any of embodiments 1-33 or an oligomeric duplex of embodiment 34.

Embodiment 36. A pharmaceutical composition comprising an oligomeric compound of any of embodiments 1-33 or an oligomeric duplex of embodiment 34 and a pharmaceutically acceptable carrier or diluent.

Embodiment 37. A modified oligonucleotide according to the following formula:

or a salt thereof.

Embodiment 38. A modified oligonucleotide according to the following formula:

or a salt thereof.

Embodiment 39. A modified oligonucleotide according to the following formula:

or a salt thereof.

Embodiment 40. A modified oligonucleotide according to the following formula:

or a salt thereof.

Embodiment 41. A modified oligonucleotide according to the following formula:

or a salt thereof.

Embodiment 42. A modified oligonucleotide according to the following formula:

or a salt thereof.

Embodiment 43. The modified oligonucleotide of any of embodiments 37-42, which is a sodium salt of the formula.

Embodiment 44. A modified oligonucleotide according to the following formula:

Embodiment 45. A modified oligonucleotide according to the following formula:

Embodiment 46. A modified oligonucleotide according to the following formula:

Embodiment 47. A modified oligonucleotide according to the following formula:

Embodiment 48. A modified oligonucleotide according to the following formula:

Embodiment 49. A modified oligonucleotide according to the following formula:

Embodiment 50. A chirally enriched population of the modified oligonucleotide of any of embodiments 37-49 wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having a particular stereochemical configuration.

Embodiment 51. The chirally enriched population of embodiment 50, wherein the population is enriched for a modified oligonucleotide comprising at least one particular phosphorothioate internucleoside linkage having the (Sp) configuration.

Embodiment 52. The chirally enriched population of embodiment 50 or 51, wherein the population is enriched for modified oligonucleotides having at least one particular phosphorothioate internucleoside linkage having the (Rp) configuration.

Embodiment 53. The chirally enriched population of embodiment 50, wherein the population is enriched for modified oligonucleotides having a particular, independently selected stereochemical configuration at each phosphorothioate internucleoside linkage

Embodiment 54. The chirally enriched population of embodiment 53, wherein the population is enriched for modified oligonucleotides having the (Sp) configuration at each phosphorothioate internucleoside linkage.

Embodiment 55. The chirally enriched population of embodiment 53, wherein the population is enriched for modified oligonucleotides having the (Rp) configuration at each phosphorothioate internucleoside linkage.

Embodiment 56. The chirally enriched population of embodiment 50 or embodiment 53 wherein the population is enriched for modified oligonucleotides having at least 3 contiguous phosphorothioate internucleoside linkages in the Sp-Sp-Rp configuration, in the 5′ to 3′ direction.

Embodiment 57. A population of modified oligonucleotides of any of embodiments 37-49, wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.

Embodiment 58. A pharmaceutical composition comprising the modified oligonucleotide of any of embodiments 37-49 and a pharmaceutically acceptable diluent or carrier.

Embodiment 59. The pharmaceutical composition of embodiment 58, wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid.

Embodiment 60. The pharmaceutical composition of embodiment 59, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.

Embodiment 61. A method comprising administering to an animal a pharmaceutical composition of any of embodiments 36 or 58-60.

Embodiment 62. A method of treating a disease associated with LRRK2 comprising administering to an individual having or at risk for developing a disease associated with LRRK2 a therapeutically effective amount of a pharmaceutical composition according to any of embodiments 36 or 58-60; and thereby treating the disease associated with LRRK2.

Embodiment 63. The method of embodiment 62, wherein the disease associated with LRRK2 is a neurodegenerative disease.

Embodiment 64. The method of embodiment 63, wherein the neurodegenerative disease is Parkinson's disease.

Embodiment 65. The method of embodiment 64, wherein at least one symptom or hallmark of the neurodegenerative disease is ameliorated.

Embodiment 66. The method of embodiment 65, wherein the symptom or hallmark is any of ataxia, neuropathy, and aggregate formation.

Embodiment 67. An oligomeric compound comprising a modified oligonucleotide according to the following formula:

Ges mCeo Teo mCeo Aes Tds Ads Tds mCds Tds Ads Ads Ads Gds Ads mCeo mCeo Ges mCes Ae (SEQ ID NO: 222); wherein,

A=an adenine nucleobase,

mC=a 5-methyl cytosine nucleobase,

G=a guanine nucleobase,

T=a thymine nucleobase,

e=a 2′-MOE modified sugar,

d=a 2′-deoxyribose sugar,

s=a phosphorothioate internucleoside linkage, and

o=a phosphodiester internucleoside linkage.

Embodiment 68. An oligomeric compound comprising a modified oligonucleotide according to the following formula:

Tes mCeo Aeo mCeo mCes Ads mCds Ads Ads Ads mCds Tds mCds Ads Tds Geo Geo Aes mCes Te (SEQ ID NO: 888); wherein,

A=an adenine nucleobase,

mC=a 5-methyl cytosine nucleobase,

G=a guanine nucleobase,

T=a thymine nucleobase,

e=a 2′-MOE modified sugar,

d=a 2′-deoxyribose sugar,

s=a phosphorothioate internucleoside linkage, and

o=a phosphodiester internucleoside linkage.

Embodiment 69. An oligomeric compound comprising a modified oligonucleotide according to the following formula:

Aes mCeo mCeo mCeo Tes Tds Tds mCds mCds Ads Tds Gds Tds Gds Ads Aeo mCeo Aes Tes Te (SEQ ID NO: 1431); wherein,

A=an adenine nucleobase,

mC=a 5-methyl cytosine nucleobase,

G=a guanine nucleobase,

T=a thymine nucleobase,

e=a 2′-MOE modified sugar,

d=a 2′-deoxyribose sugar,

s=a phosphorothioate internucleoside linkage, and

o=a phosphodiester internucleoside linkage.

Embodiment 70. An oligomeric compound comprising a modified oligonucleotide according to the following formula:

Aes mCeo Geo mCeo Aes mCds Tds Tds Ads Ads mCds Ads Ads Tds Ads Teo mCeo Aes Tes Ae (SEQ ID NO: 3590); wherein,

A=an adenine nucleobase,

mC=a 5-methyl cytosine nucleobase,

G=a guanine nucleobase,

T=a thymine nucleobase,

e=a 2′-MOE modified sugar,

d=a 2′-deoxyribose sugar,

s=a phosphorothioate internucleoside linkage, and

o=a phosphodiester internucleoside linkage.

Embodiment 71. An oligomeric compound comprising a modified oligonucleotide according to the following formula: Aes Geo mCeo Aeo Aes Tds mCds Ads Tds Tds Gds Gds Tds Ads Gds mCeo Aeo Tes Aes mCe (SEQ ID NO: 3385); wherein,

-   -   A=an adenine nucleobase,     -   mC=a 5-methyl cytosine nucleobase,     -   G=a guanine nucleobase,     -   T=a thymine nucleobase,     -   e=a 2′-MOE modified sugar,     -   d=a 2′-deoxyribose sugar,     -   s=a phosphorothioate internucleoside linkage, and     -   o=a phosphodiester internucleoside linkage.

Embodiment 72. An oligomeric compound comprising a modified oligonucleotide according to the following formula: mCes Geo mCes Aes mCes Tds Tds Ads Ads mCds Ads Ads Tds Ads Tds mCes Aeo Tes Aes Te (SEQ ID NO: 852); wherein,

-   -   A=an adenine nucleobase,     -   mC=a 5-methyl cytosine nucleobase,     -   G=a guanine nucleobase,     -   T=a thymine nucleobase,     -   e=a 2′-MOE modified sugar,     -   d=a 2′-deoxyribose sugar,     -   s=a phosphorothioate internucleoside linkage, and     -   o=a phosphodiester internucleoside linkage.

Embodiment 73. The oligomeric compound of embodiment 3, wherein the modified oligonucleotide is an RNAi compound.

Embodiment 74. The oligomeric compound of embodiment 73, wherein the RNAi compound is an ssRNA or an siRNA.

I. Certain Oligonucleotides

In certain embodiments, provided herein are oligomeric compounds comprising oligonucleotides, which consist of linked nucleosides. Oligonucleotides may be unmodified oligonucleotides (RNA or DNA) or may be modified oligonucleotides. Modified oligonucleotides comprise at least one modification relative to unmodified RNA or DNA. That is, modified oligonucleotides comprise at least one modified nucleoside (comprising a modified sugar moiety and/or a modified nucleobase) and/or at least one modified internucleoside linkage.

A. Certain Modified Nucleosides

Modified nucleosides comprise a modified sugar moiety or a modified nucleobase or both a modified sugar moiety and a modified nucleobase.

1. Certain Sugar Moieties

In certain embodiments, modified sugar moieties are non-bicyclic modified sugar moieties. In certain embodiments, modified sugar moieties are bicyclic or tricyclic sugar moieties. In certain embodiments, modified sugar moieties are sugar surrogates. Such sugar surrogates may comprise one or more substitutions corresponding to those of other types of modified sugar moieties.

In certain embodiments, modified sugar moieties are non-bicyclic modified sugar moieties comprising a furanosyl ring with one or more substituent groups none of which bridges two atoms of the furanosyl ring to form a bicyclic structure. Such non bridging substituents may be at any position of the furanosyl, including but not limited to substituents at the 2′, 4′, and/or 5′ positions. In certain embodiments one or more non-bridging substituent of non-bicyclic modified sugar moieties is branched. Examples of 2′-substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to: 2′-F, 2′-OCH₃ (“OMe” or “O-methyl”), and 2′-O(CH₂)₂OCH₃ (“MOE”). In certain embodiments, 2′-substituent groups are selected from among: halo, allyl, amino, azido, SH, CN, OCN, CF₃, OCF₃, alkoxy, O—C₁-C₁₀ substituted alkoxy, O—C₁-C₁₀alkyl, O—C₁-C₁₀ substituted alkyl, S-alkyl, N(R_(m))-alkyl, O-alkenyl, S-alkenyl, N(R_(m))-alkenyl, O-alkynyl, S-alkynyl, N(R_(m))-alkynyl, O-alkylenyl-O-alkyl, alkynyl, alkaryl, aralkyl, O-alkaryl, O-aralkyl, O(CH₂)₂SCH₃, O(CH₂)₂ON(R_(m))(R_(n)) or OCH₂C(═O)—N(R_(m))(R_(n)), where each R_(m) and R_(n) is, independently, H, an amino protecting group, or substituted or unsubstituted C₁-C₁₀ alkyl, and the 2′-substituent groups described in Cook et al., U.S. Pat. No. 6,531,584; Cook et al., U.S. Pat. No. 5,859,221; and Cook et al., U.S. Pat. No. 6,005,087. Certain embodiments of these 2′-substituent groups can be further substituted with one or more substituent groups independently selected from among: hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro (NO₂), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl and alkynyl. Examples of 4′-substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015/106128. Examples of 5′-substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to: 5-methyl (R or S), 5′-vinyl, and 5′-methoxy. In certain embodiments, non-bicyclic modified sugar moieties comprise more than one non-bridging sugar substituent, for example, 2′-F-5′-methyl sugar moieties and the modified sugar moieties and modified nucleosides described in Migawa et al., WO 2008/101157 and Rajeev et al., US2013/0203836.).

In certain embodiments, a 2′-substituted non-bicyclic modified nucleoside comprises a sugar moiety comprising a non-bridging 2′-substituent group selected from: F, NH₂, N₃, OCF₃, OCH₃, O(CH₂)₃NH₂, CH₂CH═CH₂, OCH₂CH═CH₂, OCH₂CH₂OCH₃, O(CH₂)₂SCH₃, O(CH₂)₂ON(R_(m))(R_(n)), O(CH₂)₂O(CH₂)₂N(CH₃)₂, and N-substituted acetamide (OCH₂C(═O)—N(R_(m))(R_(n)), where each R_(m) and R_(n) is, independently, H, an amino protecting group, or substituted or unsubstituted C₁-C₁₀ alkyl.

In certain embodiments, a 2′-substituted nucleoside non-bicyclic modified nucleoside comprises a sugar moiety comprising a non-bridging 2′-substituent group selected from: F, OCF₃, OCH₃, OCH₂CH₂OCH₃, O(CH₂)₂SCH₃, O(CH₂)₂ON(CH₃)₂, O(CH₂)₂O(CH₂)₂N(CH₃)₂, and OCH₂C(═O)—N(H)CH₃ (“NMA”).

In certain embodiments, a 2′-substituted non-bicyclic modified nucleoside comprises a sugar moiety comprising a non-bridging 2′-substituent group selected from: F, OCH₃, and OCH₂CH₂OCH₃.

Certain modified sugar moieties comprise a substituent that bridges two atoms of the furanosyl ring to form a second ring, resulting in a bicyclic sugar moiety. In certain such embodiments, the bicyclic sugar moiety comprises a bridge between the 4′ and the 2′ furanose ring atoms. Examples of such 4′ to 2′ bridging sugar substituents include but are not limited to: 4′-CH₂-2′, 4′-(CH₂)₂-2′, 4′-(CH₂)₃-2′, (“LNA”), 4′-(CH₂)₂—O-2′ (“ENA”), 4′-CH(CH₃)—O-2′ (referred to as “constrained ethyl” or “cEt”), 4′-CH₂—N(R)-2′, 4′-CH(CH₂OCH₃)—O-2′ (“constrained MOE” or “cMOE”) and analogs thereof (see, e.g., Seth et al., U.S. Pat. No. 7,399,845, Bhat et al., U.S. Pat. No. 7,569,686, Swayze et al., U.S. Pat. No. 7,741,457, and Swayze et al., U.S. Pat. No. 8,022,193), 4′-C(CH₃)(CH₃)—O-2′ and analogs thereof (see, e.g., Seth et al., U.S. Pat. No. 8,278,283), 4′-CH₂—N(OCH₃)-2′ and analogs thereof (see, e.g., Prakash et al., U.S. Pat. No. 8,278,425), 4′-CH₂—O—N(CH₃)-2′ (see, e.g., Allerson et al., U.S. Pat. No. 7,696,345 and Allerson et al., U.S. Pat. No. 8,124,745), 4′-CH₂—C(H)(CH₃)-2′ (see, e.g., Zhou, et al., J. Org. Chem., 2009, 74, 118-134), 4′-CH₂—C(═CH₂)-2′ and analogs thereof (see e.g., Seth et al., U.S. Pat. No. 8,278,426), 4′-C(R_(a)R_(b))—N(R)—O-2′, 4′-C(R_(a)R_(b))—O—N(R)-2′, 4′-CH₂—O—N(R)-2′, and 4′-CH₂—N(R)—O- 2′, wherein each R, R_(a), and R_(b) is, independently, H, a protecting group, or C₁-C₁₂ alkyl (see, e.g. Imanishi et al., U.S. Pat. No. 7,427,672).

In certain embodiments, such 4′ to 2′ bridges independently comprise from 1 to 4 linked groups independently selected from: —[C(R_(a))(R_(b))]_(n)—, —[C(R_(a))(R_(b))]_(n)O—, —C(R_(a))═C(R_(b))—, —C(R_(a))═N—, —C(═NR_(a))—, —C(═O)—, —C(═S)—, —O—, —Si(R_(a))₂—, —S(═O)_(x)—, and —N(R_(a))—;

wherein:

x is 0, 1, or 2;

n is 1, 2, 3, or 4;

each R_(a) and R_(b) is, independently, H, a protecting group, hydroxyl, C₁-C₁₂ alkyl, substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, substituted C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, substituted C₂-C₁₂ alkynyl, C₅-C₂₀ aryl, substituted C₅-C₂₀ aryl, heterocycle radical, substituted heterocycle radical, heteroaryl, substituted heteroaryl, C₅-C₇ alicyclic radical, substituted C₅-C₇ alicyclic radical, halogen, OJ₁, NJ₁J₂, SJ₁, N₃, COOJ₁, acyl (C(═O)—H), substituted acyl, CN, sulfonyl (S(═O)₂-J₁), or sulfoxyl (S(═O)-J₁); and

each J₁ and J₂ is, independently, H, C₁-C₁₂ alkyl, substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, substituted C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, substituted C₂-C₁₂ alkynyl, C₅-C₂₀ aryl, substituted C₅-C₂₀ aryl, acyl (C(═O)—H), substituted acyl, a heterocycle radical, a substituted heterocycle radical, C₁-C₁₂ aminoalkyl, substituted C₁-C₁₂ aminoalkyl, or a protecting group.

Additional bicyclic sugar moieties are known in the art, see, for example: Freier et al., Nucleic Acids Research, 1997, 25(22), 4429-4443, Albaek et al., J Org. Chem., 2006, 71, 7731-7740, Singh et al., Chem. Commun., 1998, 4, 455-456; Koshkin et al., Tetrahedron, 1998, 54, 3607-3630; Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222; Singh et al., J. Org. Chem., 1998, 63, 10035-10039; Srivastava et al., J Am. Chem. Soc., 2007, 129, 8362-8379; Wengel et a., U.S. Pat. No. 7,053,207; Imanishi et al., U.S. Pat. No. 6,268,490; Imanishi et al. U.S. Pat. No. 6,770,748; Imanishi et al., U.S. RE44,779; Wengel et al., U.S. Pat. No. 6,794,499; Wengel et al., U.S. Pat. No. 6,670,461; Wengel et al., U.S. Pat. No. 7,034,133; Wengel et al., U.S. Pat. No. 8,080,644; Wengel et al., U.S. Pat. No. 8,034,909; Wengel et al., U.S. Pat. No. 8,153,365; Wengel et al., U.S. Pat. No. 7,572,582; and Ramasamy et al., U.S. Pat. No. 6,525,191; Torsten et al., WO 2004/106356; Wengel et al., WO 1999/014226; Seth et al., WO 2007/134181; Seth et al., U.S. Pat. No. 7,547,684; Seth et al., U.S. Pat. No. 7,666,854; Seth et al., U.S. Pat. No. 8,088,746; Seth et al., U.S. Pat. No. 7,750,131; Seth et al., U.S. Pat. No. 8,030,467; Seth et al., U.S. Pat. No. 8,268,980; Seth et al., U.S. Pat. No. 8,546,556; Seth et al., U.S. Pat. No. 8,530,640; Migawa et al., U.S. Pat. No. 9,012,421; Seth et al., U.S. Pat. No. 8,501,805; and U.S. Patent Publication Nos. Allerson et al., US2008/0039618 and Migawa et al., US2015/0191727.

In certain embodiments, bicyclic sugar moieties and nucleosides incorporating such bicyclic sugar moieties are further defined by isomeric configuration. For example, an LNA nucleoside (described herein) may be in the α-L configuration or in the β-D configuration.

α-L-methyleneoxy (4′-CH₂—O-2′) or α-L-LNA bicyclic nucleosides have been incorporated into oligonucleotides that showed antisense activity (Frieden et al., Nucleic Acids Research, 2003, 21, 6365-6372). Herein, general descriptions of bicyclic nucleosides include both isomeric configurations. When the positions of specific bicyclic nucleosides (e.g., LNA or cEt) are identified in exemplified embodiments herein, they are in the β-D configuration, unless otherwise specified.

In certain embodiments, modified sugar moieties comprise one or more non-bridging sugar substituent and one or more bridging sugar substituent (e.g., 5′-substituted and 4′-2′ bridged sugars).

In certain embodiments, modified sugar moieties are sugar surrogates. In certain such embodiments, the oxygen atom of the sugar moiety is replaced, e.g., with a sulfur, carbon or nitrogen atom. In certain such embodiments, such modified sugar moieties also comprise bridging and/or non-bridging substituents as described herein. For example, certain sugar surrogates comprise a 4′-sulfur atom and a substitution at the 2′-position (see, e.g., Bhat et al., U.S. Pat. No. 7,875,733 and Bhat et al., U.S. Pat. No. 7,939,677) and/or the 5′ position.

In certain embodiments, sugar surrogates comprise rings having other than 5 atoms. For example, in certain embodiments, a sugar surrogate comprises a six-membered tetrahydropyran (“THP”). Such tetrahydropyrans may be further modified or substituted. Nucleosides comprising such modified tetrahydropyrans include but are not limited to hexitol nucleic acid (“HNA”), anitol nucleic acid (“ANA”), manitol nucleic acid (“MNA”) (see, e.g., Leumann, C J. Bioorg. & Med. Chem. 2002, 10, 841-854), fluoro HNA:

(“F-HNA”, see e.g. Swayze et al., U.S. Pat. No. 8,088,904; Swayze et al., U.S. Pat. No. 8,440,803; Swayze et al., U.S. Pat. No. 8,796,437; and Swayze et al., U.S. Pat. No. 9,005,906; F-HNA can also be referred to as a F-THP or 3′-fluoro tetrahydropyran), and nucleosides comprising additional modified THP compounds having the formula:

wherein, independently, for each of said modified THP nucleoside:

Bx is a nucleobase moiety;

T₃ and T₄ are each, independently, an internucleoside linking group linking the modified THP nucleoside to the remainder of an oligonucleotide or one of T₃ and T₄ is an internucleoside linking group linking the modified THP nucleoside to the remainder of an oligonucleotide and the other of T₃ and T₄ is H, a hydroxyl protecting group, a linked conjugate group, or a 5′ or 3′-terminal group;

q₁, q₂, q₃, q₄, q₅, q₆ and q₇ are each, independently, H, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl, or substituted C₂-C₆ alkynyl; and

each of R₁ and R₂ is independently selected from among: hydrogen, halogen, substituted or unsubstituted alkoxy, NJ₁J₂, SJ₁, N₃, OC(═X)J₁, OC(═X)NJ₁J₂, NJ₃C(═X)NJ₁J₂, and CN, wherein X is O, S or NJ₁, and each J₁, J₂, and J₃ is, independently, H or C₁-C₆ alkyl.

In certain embodiments, modified THP nucleosides are provided wherein q₁, q₂, q₃, q₄, q₅, q₆ and q₇ are each H. In certain embodiments, at least one of q₁, q₂, q₃, q₄, q₅, q₆ and q₇ is other than H. In certain embodiments, at least one of q₁, q₂, q₃, q₄, q₅, q₆ and q₇ is methyl. In certain embodiments, modified THP nucleosides are provided wherein one of R₁ and R₂ is F. In certain embodiments, R₁ is F and R₂ is H, in certain embodiments, R₁ is methoxy and R₂ is H, and in certain embodiments, R₁ is methoxyethoxy and R₂ is H.

In certain embodiments, sugar surrogates comprise rings having more than 5 atoms and more than one heteroatom. For example, nucleosides comprising morpholino sugar moieties and their use in oligonucleotides have been reported (see, e.g., Braasch et al., Biochemistry, 2002, 41, 4503-4510 and Summerton et al., U.S. Pat. No. 5,698,685; Summerton et al., U.S. Pat. No. 5,166,315; Summerton et al., U.S. Pat. No. 5,185,444; and Summerton et al., U.S. Pat. No. 5,034,506). As used here, the term “morpholino” means a sugar surrogate having the following structure:

In certain embodiments, morpholinos may be modified, for example by adding or altering various substituent groups from the above morpholino structure. Such sugar surrogates are referred to herein as “modified morpholinos.”

In certain embodiments, sugar surrogates comprise acyclic moieties. Examples of nucleosides and oligonucleotides comprising such acyclic sugar surrogates include but are not limited to: peptide nucleic acid (“PNA”), acyclic butyl nucleic acid (see, e.g., Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and nucleosides and oligonucleotides described in Manoharan et al., WO2011/133876.

Many other bicyclic and tricyclic sugar and sugar surrogate ring systems are known in the art that can be used in modified nucleosides.

2. Certain Modified Nucleobases

In certain embodiments, modified oligonucleotides comprise one or more nucleoside comprising an unmodified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleoside comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleoside that does not comprise a nucleobase, referred to as an abasic nucleoside.

In certain embodiments, modified nucleobases are selected from: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and N-2, N-6 and O-6 substituted purines. In certain embodiments, modified nucleobases are selected from: 2-aminopropyladenine, 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl (—C≡C—CH₃) uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo, particularly 5-bromo, 5-trifluoromethyl, 5-halouracil, and 5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size-expanded bases, and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines, such as 1,3-diazaphenoxazine-2-one, 1,3-diazaphenothiazine-2-one and 9-(2-aminoethoxy)-1,3-diazaphenoxazine-2-one (G-clamp). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deazaadenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. Further nucleobases include those disclosed in Merigan et al., U.S. Pat. No. 3,687,808, those disclosed in The Concise Encyclopedia Of Polymer Science And Engineering, Kroschwitz, J. I., Ed., John Wiley & Sons, 1990, 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, Y. S., Chapter 15, Antisense Research and Applications, Crooke, S. T. and Lebleu, B., Eds., CRC Press, 1993, 273-288; and those disclosed in Chapters 6 and 15, Antisense Drug Technology, Crooke S. T., Ed., CRC Press, 2008, 163-166 and 442-443.

Publications that teach the preparation of certain of the above noted modified nucleobases as well as other modified nucleobases include without limitation, Manohara et al., US2003/0158403; Manoharan et al., US2003/0175906; Dinh et al., U.S. Pat. No. 4,845,205; Spielvogel et al., U.S. Pat. No. 5,130,302; Rogers et al., U.S. Pat. No. 5,134,066; Bischofberger et al., U.S. Pat. No. 5,175,273; Urdea et al., U.S. Pat. No. 5,367,066; Benner et al., U.S. Pat. No. 5,432,272; Matteucci et al., U.S. Pat. No. 5,434,257; Gmeiner et al., U.S. Pat. No. 5,457,187; Cook et al., U.S. Pat. No. 5,459,255; Froehler et al., U.S. Pat. No. 5,484,908; Matteucci et al., U.S. Pat. No. 5,502,177; Hawkins et al., U.S. Pat. No. 5,525,711; Haralambidis et al., U.S. Pat. No. 5,552,540; Cook et al., U.S. Pat. No. 5,587,469; Froehler et al., U.S. Pat. No. 5,594,121; Switzer et al., U.S. Pat. No. 5,596,091; Cook et al., U.S. Pat. No. 5,614,617; Froehler et al., U.S. Pat. No. 5,645,985; Cook et al., U.S. Pat. No. 5,681,941; Cook et al., U.S. Pat. No. 5,811,534; Cook et al., U.S. Pat. No. 5,750,692; Cook et al., U.S. Pat. No. 5,948,903; Cook et al., U.S. Pat. No. 5,587,470; Cook et al., U.S. Pat. No. 5,457,191; Matteucci et al., U.S. Pat. No. 5,763,588; Froehler et al., U.S. Pat. No. 5,830,653; Cook et al., U.S. Pat. No. 5,808,027; Cook et al., 6,166,199; and Matteucci et al., U.S. Pat. No. 6,005,096.

3. Certain Modified Internucleoside Linkages

In certain embodiments, nucleosides of modified oligonucleotides may be linked together using any internucleoside linkage. The two main classes of internucleoside linking groups are defined by the presence or absence of a phosphorus atom. Representative phosphorus-containing internucleoside linkages include but are not limited to phosphates, which contain a phosphodiester bond (“P═O”) (also referred to as unmodified or naturally occurring linkages), phosphotriesters, methylphosphonates, phosphoramidates, and phosphorothioates (“P═S”), and phosphorodithioates (“HS—P═S”). Representative non-phosphorus containing internucleoside linking groups include but are not limited to methylenemethylimino (—CH₂—N(CH₃)—O—CH₂—), thiodiester, thionocarbamate (—O—C(═O)(NH)—S—); siloxane (—O—SiH₂—O—); and N,N′-dimethylhydrazine (—CH₂—N(CH₃)—N(CH₃)—). Modified internucleoside linkages, compared to naturally occurring phosphate linkages, can be used to alter, typically increase, nuclease resistance of the oligonucleotide. In certain embodiments, internucleoside linkages having a chiral atom can be prepared as a racemic mixture, or as separate enantiomers. Methods of preparation of phosphorous-containing and non-phosphorous-containing internucleoside linkages are well known to those skilled in the art.

Representative internucleoside linkages having a chiral center include but are not limited to alkylphosphonates and phosphorothioates. Modified oligonucleotides comprising internucleoside linkages having a chiral center can be prepared as populations of modified oligonucleotides comprising stereorandom internucleoside linkages, or as populations of modified oligonucleotides comprising phosphorothioate linkages in particular stereochemical configurations. In certain embodiments, populations of modified oligonucleotides comprise phosphorothioate internucleoside linkages wherein all of the phosphorothioate internucleoside linkages are stereorandom. Such modified oligonucleotides can be generated using synthetic methods that result in random selection of the stereochemical configuration of each phosphorothioate linkage. Nonetheless, as is well understood by those of skill in the art, each individual phosphorothioate of each individual oligonucleotide molecule has a defined stereoconfiguration. In certain embodiments, populations of modified oligonucleotides are enriched for modified oligonucleotides comprising one or more particular phosphorothioate internucleoside linkages in a particular, independently selected stereochemical configuration. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 65% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 70% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 80% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 90% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 99% of the molecules in the population. Such chirally enriched populations of modified oligonucleotides can be generated using synthetic methods known in the art, e.g., methods described in Oka et al., JACCS 125, 8307 (2003), Wan et al. Nuc. Acid. Res. 42, 13456 (2014), and WO 2017/015555. In certain embodiments, a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one indicated phosphorothioate in the (Sp) configuration. In certain embodiments, a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one phosphorothioate in the (Rp) configuration. In certain embodiments, modified oligonucleotides comprising (Rp) and/or (Sp) phosphorothioates comprise one or more of the following formulas, respectively, wherein “B” indicates a nucleobase:

Unless otherwise indicated, chiral internucleoside linkages of modified oligonucleotides described herein can be stereorandom or in a particular stereochemical configuration.

Neutral internucleoside linkages include, without limitation, phosphotriesters, methylphosphonates, MMI (3′-CH₂—N(CH₃)—O-5′), amide-3 (3′-CH₂—C(═O)—N(H)-5′), amide-4 (3′-CH₂—N(H)—C(═O)-5′), formacetal (3′-O—CH₂—O-5′), methoxypropyl, and thioformacetal (3′-S—CH₂—O-5′). Further neutral internucleoside linkages include nonionic linkages comprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester and amides (See for example: Carbohydrate Modifications in Antisense Research; Y. S. Sanghvi and P. D. Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Further neutral internucleoside linkages include nonionic linkages comprising mixed N, O, S and CH₂ component parts.

B. Certain Motifs

In certain embodiments, modified oligonucleotides comprise one or more modified nucleosides comprising a modified sugar moiety. In certain embodiments, modified oligonucleotides comprise one or more modified nucleosides comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more modified internucleoside linkage. In such embodiments, the modified, unmodified, and differently modified sugar moieties, nucleobases, and/or internucleoside linkages of a modified oligonucleotide define a pattern or motif. In certain embodiments, the patterns of sugar moieties, nucleobases, and internucleoside linkages are each independent of one another. Thus, a modified oligonucleotide may be described by its sugar motif, nucleobase motif and/or internucleoside linkage motif (as used herein, nucleobase motif describes the modifications to the nucleobases independent of the sequence of nucleobases).

1. Certain Sugar Motifs

In certain embodiments, oligonucleotides comprise one or more type of modified sugar and/or unmodified sugar moiety arranged along the oligonucleotide or region thereof in a defined pattern or sugar motif. In certain instances, such sugar motifs include but are not limited to any of the sugar modifications discussed herein.

In certain embodiments, modified oligonucleotides comprise or consist of a region having a gapmer motif, which is defined by two external regions or “wings” and a central or internal region or “gap.” The three regions of a gapmer motif (the 5′-wing, the gap, and the 3′-wing) form a contiguous sequence of nucleosides wherein at least some of the sugar moieties of the nucleosides of each of the wings differ from at least some of the sugar moieties of the nucleosides of the gap. Specifically, at least the sugar moieties of the nucleosides of each wing that are closest to the gap (the 3′-most nucleoside of the 5′-wing and the 5′-most nucleoside of the 3′-wing) differ from the sugar moiety of the neighboring gap nucleosides, thus defining the boundary between the wings and the gap (i.e., the wing/gap junction). In certain embodiments, the sugar moieties within the gap are the same as one another. In certain embodiments, the gap includes one or more nucleoside having a sugar moiety that differs from the sugar moiety of one or more other nucleosides of the gap. In certain embodiments, the sugar motifs of the two wings are the same as one another (symmetric gapmer). In certain embodiments, the sugar motif of the 5′-wing differs from the sugar motif of the 3′-wing (asymmetric gapmer).

In certain embodiments, the wings of a gapmer comprise 1-5 nucleosides. In certain embodiments, each nucleoside of each wing of a gapmer is a modified nucleoside. In certain embodiments, at least one nucleoside of each wing of a gapmer is a modified nucleoside. In certain embodiments, at least two nucleosides of each wing of a gapmer are modified nucleosides. In certain embodiments, at least three nucleosides of each wing of a gapmer are modified nucleosides. In certain embodiments, at least four nucleosides of each wing of a gapmer are modified nucleosides.

In certain embodiments, the gap of a gapmer comprises 7-12 nucleosides. In certain embodiments, each nucleoside of the gap of a gapmer is an unmodified 2′-deoxy nucleoside. In certain embodiments, at least one nucleoside of the gap of a gapmer is a modified nucleoside.

In certain embodiments, the gapmer is a deoxy gapmer. In certain embodiments, the nucleosides on the gap side of each wing/gap junction are unmodified 2′-deoxy nucleosides and the nucleosides on the wing sides of each wing/gap junction are modified nucleosides. In certain embodiments, each nucleoside of the gap is an unmodified 2′-deoxy nucleoside. In certain embodiments, each nucleoside of each wing of a gapmer is a modified nucleoside.

In certain embodiments, modified oligonucleotides comprise or consist of a region having a fully modified sugar motif. In such embodiments, each nucleoside of the fully modified region of the modified oligonucleotide comprises a modified sugar moiety. In certain embodiments, each nucleoside of the entire modified oligonucleotide comprises a modified sugar moiety. In certain embodiments, modified oligonucleotides comprise or consist of a region having a fully modified sugar motif, wherein each nucleoside within the fully modified region comprises the same modified sugar moiety, referred to herein as a uniformly modified sugar motif. In certain embodiments, a fully modified oligonucleotide is a uniformly modified oligonucleotide. In certain embodiments, each nucleoside of a uniformly modified comprises the same 2′-modification.

Herein, the lengths (number of nucleosides) of the three regions of a gapmer may be provided using the notation [# of nucleosides in the 5′-wing]-[# of nucleosides in the gap]-[# of nucleosides in the 3′-wing]. Thus, a 5-10-5 gapmer consists of 5 linked nucleosides in each wing and 10 linked nucleosides in the gap. Where such nomenclature is followed by a specific modification, that modification is the modification in each sugar moiety of each wing and the gap nucleosides comprise unmodified deoxynucleosides sugars. Thus, a 5-10-5 MOE gapmer consists of 5 linked MOE modified nucleosides in the 5′-wing, 10 linked deoxynucleosides in the gap, and 5 linked MOE nucleosides in the 3′-wing.

In certain embodiments, modified oligonucleotides are 5-10-5 MOE gapmers. In certain embodiments, modified oligonucleotides are 3-10-3 BNA gapmers. In certain embodiments, modified oligonucleotides are 3-10-3 cEt gapmers. In certain embodiments, modified oligonucleotides are 3-10-3 LNA gapmers.

2. Certain Nucleobase Motifs

In certain embodiments, oligonucleotides comprise modified and/or unmodified nucleobases arranged along the oligonucleotide or region thereof in a defined pattern or motif. In certain embodiments, each nucleobase is modified. In certain embodiments, none of the nucleobases are modified. In certain embodiments, each purine or each pyrimidine is modified. In certain embodiments, each adenine is modified. In certain embodiments, each guanine is modified. In certain embodiments, each thymine is modified. In certain embodiments, each uracil is modified. In certain embodiments, each cytosine is modified. In certain embodiments, some or all of the cytosine nucleobases in a modified oligonucleotide are 5-methyl cytosines. In certain embodiments, all of the cytosine nucleobases are 5-methyl cytosines and all of the other nucleobases of the modified oligonucleotide are unmodified nucleobases.

In certain embodiments, modified oligonucleotides comprise a block of modified nucleobases. In certain such embodiments, the block is at the 3′-end of the oligonucleotide. In certain embodiments the block is within 3 nucleosides of the 3′-end of the oligonucleotide. In certain embodiments, the block is at the 5′-end of the oligonucleotide. In certain embodiments the block is within 3 nucleosides of the 5′-end of the oligonucleotide.

In certain embodiments, oligonucleotides having a gapmer motif comprise a nucleoside comprising a modified nucleobase. In certain such embodiments, one nucleoside comprising a modified nucleobase is in the central gap of an oligonucleotide having a gapmer motif. In certain such embodiments, the sugar moiety of said nucleoside is a 2′-deoxyribosyl moiety. In certain embodiments, the modified nucleobase is selected from: a 2-thiopyrimidine and a 5-propynepyrimidine.

3. Certain Internucleoside Linkage Motifs

In certain embodiments, oligonucleotides comprise modified and/or unmodified internucleoside linkages arranged along the oligonucleotide or region thereof in a defined pattern or motif. In certain embodiments, each internucleoside linking group is a phosphodiester internucleoside linkage (P═O). In certain embodiments, each internucleoside linking group of a modified oligonucleotide is a phosphorothioate internucleoside linkage (P═S). In certain embodiments, each internucleoside linkage of a modified oligonucleotide is independently selected from a phosphorothioate internucleoside linkage and phosphodiester internucleoside linkage. In certain embodiments, each phosphorothioate internucleoside linkage is independently selected from a stereorandom phosphorothioate a (Sp) phosphorothioate, and a (Rp) phosphorothioate. In certain embodiments, the sugar motif of a modified oligonucleotide is a gapmer and the internucleoside linkages within the gap are all modified. In certain such embodiments, some or all of the internucleoside linkages in the wings are unmodified phosphodiester internucleoside linkages. In certain embodiments, the terminal internucleoside linkages are modified. In certain embodiments, the sugar motif of a modified oligonucleotide is a gapmer, and the internucleoside linkage motif comprises at least one phosphodiester internucleoside linkage in at least one wing, wherein the at least one phosphodiester linkage is not a terminal internucleoside linkage, and the remaining internucleoside linkages are phosphorothioate internucleoside linkages. In certain such embodiments, all of the phosphorothioate linkages are stereorandom. In certain embodiments, all of the phosphorothioate linkages in the wings are (Sp) phosphorothioates, and the gap comprises at least one Sp, Sp, Rp motif. In certain embodiments, populations of modified oligonucleotides are enriched for modified oligonucleotides comprising such internucleoside linkage motifs.

C. Certain Lengths

It is possible to increase or decrease the length of an oligonucleotide without eliminating activity. For example, in Woolf et al. (Proc. Natl. Acad. Sci. USA 89:7305-7309, 1992), a series of oligonucleotides 13-25 nucleobases in length were tested for their ability to induce cleavage of a target RNA in an oocyte injection model. Oligonucleotides 25 nucleobases in length with 8 or 11 mismatch bases near the ends of the oligonucleotides were able to direct specific cleavage of the target RNA, albeit to a lesser extent than the oligonucleotides that contained no mismatches. Similarly, target specific cleavage was achieved using 13 nucleobase oligonucleotides, including those with 1 or 3 mismatches.

In certain embodiments, oligonucleotides (including modified oligonucleotides) can have any of a variety of ranges of lengths. In certain embodiments, oligonucleotides consist of X to Y linked nucleosides, where X represents the fewest number of nucleosides in the range and Y represents the largest number nucleosides in the range. In certain such embodiments, X and Y are each independently selected from 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50; provided that X≤Y. For example, in certain embodiments, oligonucleotides consist of 12 to 13, 12 to 14, 12 to 15, 12 to 16, 12 to 17, 12 to 18, 12 to 19, 12 to 20, 12 to 21, 12 to 22, 12 to 23, 12 to 24, 12 to 25, 12 to 26, 12 to 27, 12 to 28, 12 to 29, 12 to 30, 13 to 14, 13 to 15, 13 to 16, 13 to 17, 13 to 18, 13 to 19, 13 to 20, 13 to 21, 13 to 22, 13 to 23, 13 to 24, 13 to 25, 13 to 26, 13 to 27, 13 to 28, 13 to 29, 13 to 30, 14 to 15, 14 to 16, 14 to 17, 14 to 18, 14 to 19, 14 to 20, 14 to 21, 14 to 22, 14 to 23, 14 to 24, 14 to 25, 14 to 26, 14 to 27, 14 to 28, 14 to 29, 14 to 30, 15 to 16, 15 to 17, 15 to 18, 15 to 19, 15 to 20, 15 to 21, 15 to 22, 15 to 23, 15 to 24, 15 to 25, 15 to 26, 15 to 27, 15 to 28, 15 to 29, 15 to 30, 16 to 17, 16 to 18, 16 to 19, 16 to 20, 16 to 21, 16 to 22, 16 to 23, 16 to 24, 16 to 25, 16 to 26, 16 to 27, 16 to 28, 16 to 29, 16 to 30, 17 to 18, 17 to 19, 17 to 20, 17 to 21, 17 to 22, 17 to 23, 17 to 24, 17 to 25, 17 to 26, 17 to 27, 17 to 28, 17 to 29, 17 to 30, 18 to 19, 18 to 20, 18 to 21, 18 to 22, 18 to 23, 18 to 24, 18 to 25, 18 to 26, 18 to 27, 18 to 28, 18 to 29, 18 to 30, 19 to 20, 19 to 21, 19 to 22, 19 to 23, 19 to 24, 19 to 25, 19 to 26, 19 to 29, 19 to 28, 19 to 29, 19 to 30, 20 to 21, 20 to 22, 20 to 23, 20 to 24, 20 to 25, 20 to 26, 20 to 27, 20 to 28, 20 to 29, 20 to 30, 21 to 22, 21 to 23, 21 to 24, 21 to 25, 21 to 26, 21 to 27, 21 to 28, 21 to 29, 21 to 30, 22 to 23, 22 to 24, 22 to 25, 22 to 26, 22 to 27, 22 to 28, 22 to 29, 22 to 30, 23 to 24, 23 to 25, 23 to 26, 23 to 27, 23 to 28, 23 to 29, 23 to 30, 24 to 25, 24 to 26, 24 to 27, 24 to 28, 24 to 29, 24 to 30, 25 to 26, 25 to 27, 25 to 28, 25 to 29, 25 to 30, 26 to 27, 26 to 28, 26 to 29, 26 to 30, 27 to 28, 27 to 29, 27 to 30, 28 to 29, 28 to 30, or 29 to 30 linked nucleosides

D. Certain Modified Oligonucleotides

In certain embodiments, the above modifications (sugar, nucleobase, internucleoside linkage) are incorporated into a modified oligonucleotide. In certain embodiments, modified oligonucleotides are characterized by their modification motifs and overall lengths. In certain embodiments, such parameters are each independent of one another. Thus, unless otherwise indicated, each internucleoside linkage of an oligonucleotide having a gapmer sugar motif may be modified or unmodified and may or may not follow the gapmer modification pattern of the sugar modifications. For example, the internucleoside linkages within the wing regions of a sugar gapmer may be the same or different from one another and may be the same or different from the internucleoside linkages of the gap region of the sugar motif. Likewise, such sugar gapmer oligonucleotides may comprise one or more modified nucleobase independent of the gapmer pattern of the sugar modifications. Unless otherwise indicated, all modifications are independent of nucleobase sequence.

E. Certain Populations of Modified Oligonucleotides

Populations of modified oligonucleotides in which all of the modified oligonucleotides of the population have the same molecular formula can be stereorandom populations or chirally enriched populations. All of the chiral centers of all of the modified oligonucleotides are stereorandom in a stereorandom population. In a chirally enriched population, at least one particular chiral center is not stereorandom in the modified oligonucleotides of the population. In certain embodiments, the modified oligonucleotides of a chirally enriched population are enriched for β-D ribosyl sugar moieties, and all of the phosphorothioate internucleoside linkages are stereorandom. In certain embodiments, the modified oligonucleotides of a chirally enriched population are enriched for both β-D ribosyl sugar moieties and at least one, particular phosphorothioate internucleoside linkage in a particular stereochemical configuration.

F. Nucleobase Sequence

In certain embodiments, oligonucleotides (unmodified or modified oligonucleotides) are further described by their nucleobase sequence. In certain embodiments oligonucleotides have a nucleobase sequence that is complementary to a second oligonucleotide or an identified reference nucleic acid, such as a target nucleic acid. In certain such embodiments, a region of an oligonucleotide has a nucleobase sequence that is complementary to a second oligonucleotide or an identified reference nucleic acid, such as a target nucleic acid. In certain embodiments, the nucleobase sequence of a region or entire length of an oligonucleotide is at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to the second oligonucleotide or nucleic acid, such as a target nucleic acid.

II. Certain Oligomeric Compounds

In certain embodiments, provided herein are oligomeric compounds, which consist of an oligonucleotide (modified or unmodified) and optionally one or more conjugate groups and/or terminal groups. Conjugate groups consist of one or more conjugate moiety and a conjugate linker which links the conjugate moiety to the oligonucleotide. Conjugate groups may be attached to either or both ends of an oligonucleotide and/or at any internal position. In certain embodiments, conjugate groups are attached to the 2′-position of a nucleoside of a modified oligonucleotide. In certain embodiments, conjugate groups that are attached to either or both ends of an oligonucleotide are terminal groups. In certain such embodiments, conjugate groups or terminal groups are attached at the 3′ and/or 5′-end of oligonucleotides. In certain such embodiments, conjugate groups (or terminal groups) are attached at the 3′-end of oligonucleotides. In certain embodiments, conjugate groups are attached near the 3′-end of oligonucleotides. In certain embodiments, conjugate groups (or terminal groups) are attached at the 5′-end of oligonucleotides. In certain embodiments, conjugate groups are attached near the 5′-end of oligonucleotides.

Examples of terminal groups include but are not limited to conjugate groups, capping groups, phosphate moieties, protecting groups, modified or unmodified nucleosides, and two or more nucleosides that are independently modified or unmodified.

A. Certain Conjugate Groups

In certain embodiments, oligonucleotides are covalently attached to one or more conjugate groups. In certain embodiments, conjugate groups modify one or more properties of the attached oligonucleotide, including but not limited to pharmacodynamics, pharmacokinetics, stability, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge and clearance. In certain embodiments, conjugate groups impart a new property on the attached oligonucleotide, e.g., fluorophores or reporter groups that enable detection of the oligonucleotide. Certain conjugate groups and conjugate moieties have been described previously, for example: cholesterol moiety (Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid (Manoharan et al., Bioorg. Med. Chem. Lett., 1994, 4, 1053-1060), a thioether, e.g., hexyl-S-tritylthiol (Manoharan et al., Ann. N. Y. Acad. Sci., 1992, 660, 306-309; Manoharan et al., Bioorg. Med. Chem. Lett., 1993, 3, 2765-2770), a thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20, 533-538), an aliphatic chain, e.g., do-decan-diol or undecyl residues (Saison-Behmoaras et al., EMBO J., 1991, 10, 1111-1118; Kabanov et al., FEBS Lett., 1990, 259, 327-330; Svinarchuk et al., Biochimie, 1993, 75, 49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654; Shea et al., Nucl. Acids Res., 1990, 18, 3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14, 969-973), or adamantane acetic acid a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264, 229-237), an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277, 923-937), a tocopherol group (Nishina et al., Molecular Therapy Nucleic Acids, 2015, 4, e220; and Nishina et al., Molecular Therapy, 2008, 16, 734-740), or a GalNAc cluster (e.g., WO2014/179620).

1. Conjugate Moieties

Conjugate moieties include, without limitation, intercalators, reporter molecules, polyamines, polyamides, peptides, carbohydrates, vitamin moieties, polyethylene glycols, thioethers, polyethers, cholesterols, thiocholesterols, cholic acid moieties, folate, lipids, phospholipids, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluoresceins, rhodamines, coumarins, fluorophores, and dyes.

In certain embodiments, a conjugate moiety comprises an active drug substance, for example, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fen-bufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid, folinic acid, a benzothiadiazide, chlorothiazide, a diazepine, indo-methicin, a barbiturate, a cephalosporin, a sulfa drug, an antidiabetic, an antibacterial or an antibiotic.

2. Conjugate Linkers

Conjugate moieties are attached to oligonucleotides through conjugate linkers. In certain oligomeric compounds, the conjugate linker is a single chemical bond (i.e., the conjugate moiety is attached directly to an oligonucleotide through a single bond). In certain embodiments, the conjugate linker comprises a chain structure, such as a hydrocarbyl chain, or an oligomer of repeating units such as ethylene glycol, nucleosides, or amino acid units.

In certain embodiments, a conjugate linker comprises one or more groups selected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxylamino. In certain such embodiments, the conjugate linker comprises groups selected from alkyl, amino, oxo, amide and ether groups. In certain embodiments, the conjugate linker comprises groups selected from alkyl and amide groups. In certain embodiments, the conjugate linker comprises groups selected from alkyl and ether groups. In certain embodiments, the conjugate linker comprises at least one phosphorus moiety. In certain embodiments, the conjugate linker comprises at least one phosphate group. In certain embodiments, the conjugate linker includes at least one neutral linking group.

In certain embodiments, conjugate linkers, including the conjugate linkers described above, are bifunctional linking moieties, e.g., those known in the art to be useful for attaching conjugate groups to parent compounds, such as the oligonucleotides provided herein. In general, a bifunctional linking moiety comprises at least two functional groups. One of the functional groups is selected to bind to a particular site on a parent compound and the other is selected to bind to a conjugate group. Examples of functional groups used in a bifunctional linking moiety include but are not limited to electrophiles for reacting with nucleophilic groups and nucleophiles for reacting with electrophilic groups. In certain embodiments, bifunctional linking moieties comprise one or more groups selected from amino, hydroxyl, carboxylic acid, thiol, alkyl, alkenyl, and alkynyl.

Examples of conjugate linkers include but are not limited to pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) and 6-aminohexanoic acid (AHEX or AHA). Other conjugate linkers include but are not limited to substituted or unsubstituted C₁-C₁₀ alkyl, substituted or unsubstituted C₂-C₁₀ alkenyl or substituted or unsubstituted C₂-C₁₀ alkynyl, wherein a nonlimiting list of preferred substituent groups includes hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl and alkynyl.

In certain embodiments, conjugate linkers comprise 1-10 linker-nucleosides. In certain embodiments, conjugate linkers comprise 2-5 linker-nucleosides. In certain embodiments, conjugate linkers comprise exactly 3 linker-nucleosides. In certain embodiments, conjugate linkers comprise the TCA motif. In certain embodiments, such linker-nucleosides are modified nucleosides. In certain embodiments such linker-nucleosides comprise a modified sugar moiety. In certain embodiments, linker-nucleosides are unmodified. In certain embodiments, linker-nucleosides comprise an optionally protected heterocyclic base selected from a purine, substituted purine, pyrimidine or substituted pyrimidine. In certain embodiments, a cleavable moiety is a nucleoside selected from uracil, thymine, cytosine, 4-N-benzoylcytosine, 5-methyl cytosine, 4-N-benzoyl-5-methyl cytosine, adenine, 6-N-benzoyladenine, guanine and 2-N-isobutyrylguanine. It is typically desirable for linker-nucleosides to be cleaved from the oligomeric compound after it reaches a target tissue. Accordingly, linker-nucleosides are typically linked to one another and to the remainder of the oligomeric compound through cleavable bonds. In certain embodiments, such cleavable bonds are phosphodiester bonds.

Herein, linker-nucleosides are not considered to be part of the oligonucleotide. Accordingly, in embodiments in which an oligomeric compound comprises an oligonucleotide consisting of a specified number or range of linked nucleosides and/or a specified percent complementarity to a reference nucleic acid and the oligomeric compound also comprises a conjugate group comprising a conjugate linker comprising linker-nucleosides, those linker-nucleosides are not counted toward the length of the oligonucleotide and are not used in determining the percent complementarity of the oligonucleotide for the reference nucleic acid. For example, an oligomeric compound may comprise (1) a modified oligonucleotide consisting of 8-30 nucleosides and (2) a conjugate group comprising 1-10 linker-nucleosides that are contiguous with the nucleosides of the modified oligonucleotide. The total number of contiguous linked nucleosides in such an oligomeric compound is more than 30. Alternatively, an oligomeric compound may comprise a modified oligonucleotide consisting of 8-30 nucleosides and no conjugate group. The total number of contiguous linked nucleosides in such an oligomeric compound is no more than 30. Unless otherwise indicated conjugate linkers comprise no more than 10 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 5 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 3 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 2 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 1 linker-nucleoside.

In certain embodiments, it is desirable for a conjugate group to be cleaved from the oligonucleotide. For example, in certain circumstances oligomeric compounds comprising a particular conjugate moiety are better taken up by a particular cell type, but once the oligomeric compound has been taken up, it is desirable that the conjugate group be cleaved to release the unconjugated or parent oligonucleotide. Thus, certain conjugate linkers may comprise one or more cleavable moieties. In certain embodiments, a cleavable moiety is a cleavable bond. In certain embodiments, a cleavable moiety is a group of atoms comprising at least one cleavable bond. In certain embodiments, a cleavable moiety comprises a group of atoms having one, two, three, four, or more than four cleavable bonds. In certain embodiments, a cleavable moiety is selectively cleaved inside a cell or subcellular compartment, such as a lysosome. In certain embodiments, a cleavable moiety is selectively cleaved by endogenous enzymes, such as nucleases.

In certain embodiments, a cleavable bond is selected from among: an amide, an ester, an ether, one or both esters of a phosphodiester, a phosphate ester, a carbamate, or a disulfide. In certain embodiments, a cleavable bond is one or both of the esters of a phosphodiester. In certain embodiments, a cleavable moiety comprises a phosphate or phosphodiester. In certain embodiments, the cleavable moiety is a phosphate linkage between an oligonucleotide and a conjugate moiety or conjugate group.

In certain embodiments, a cleavable moiety comprises or consists of one or more linker-nucleosides. In certain such embodiments, the one or more linker-nucleosides are linked to one another and/or to the remainder of the oligomeric compound through cleavable bonds. In certain embodiments, such cleavable bonds are unmodified phosphodiester bonds. In certain embodiments, a cleavable moiety is 2′-deoxy nucleoside that is attached to either the 3′ or 5′-terminal nucleoside of an oligonucleotide by a phosphate internucleoside linkage and covalently attached to the remainder of the conjugate linker or conjugate moiety by a phosphate or phosphorothioate linkage. In certain such embodiments, the cleavable moiety is 2′-deoxyadenosine.

B. Certain Terminal Groups

In certain embodiments, oligomeric compounds comprise one or more terminal groups. In certain such embodiments, oligomeric compounds comprise a stabilized 5′-phophate. Stabilized 5′-phosphates include, but are not limited to 5′-phosphanates, including, but not limited to 5′-vinylphosphonates. In certain embodiments, terminal groups comprise one or more abasic nucleosides and/or inverted nucleosides. In certain embodiments, terminal groups comprise one or more 2′-linked nucleosides. In certain such embodiments, the 2′-linked nucleoside is an abasic nucleoside.

III. Oligomeric Duplexes

In certain embodiments, oligomeric compounds described herein comprise an oligonucleotide, having a nucleobase sequence complementary to that of a target nucleic acid. In certain embodiments, an oligomeric compound is paired with a second oligomeric compound to form an oligomeric duplex. Such oligomeric duplexes comprise a first oligomeric compound having a region complementary to a target nucleic acid and a second oligomeric compound having a region complementary to the first oligomeric compound. In certain embodiments, the first oligomeric compound of an oligomeric duplex comprises or consists of (1) a modified or unmodified oligonucleotide and optionally a conjugate group and (2) a second modified or unmodified oligonucleotide and optionally a conjugate group. Either or both oligomeric compounds of an oligomeric duplex may comprise a conjugate group. The oligonucleotides of each oligomeric compound of an oligomeric duplex may include non-complementary overhanging nucleosides.

IV. Antisense Activity

In certain embodiments, oligomeric compounds and oligomeric duplexes are capable of hybridizing to a target nucleic acid, resulting in at least one antisense activity; such oligomeric compounds and oligomeric duplexes are antisense compounds. In certain embodiments, antisense compounds have antisense activity when they reduce or inhibit the amount or activity of a target nucleic acid by 25% or more in the standard cell assay. In certain embodiments, antisense compounds selectively affect one or more target nucleic acid. Such antisense compounds comprise a nucleobase sequence that hybridizes to one or more target nucleic acid, resulting in one or more desired antisense activity and does not hybridize to one or more non-target nucleic acid or does not hybridize to one or more non-target nucleic acid in such a way that results in significant undesired antisense activity.

In certain antisense activities, hybridization of an antisense compound to a target nucleic acid results in recruitment of a protein that cleaves the target nucleic acid. For example, certain antisense compounds result in RNase H mediated cleavage of the target nucleic acid. RNase H is a cellular endonuclease that cleaves the RNA strand of an RNA:DNA duplex. The DNA in such an RNA:DNA duplex need not be unmodified DNA. In certain embodiments, described herein are antisense compounds that are sufficiently “DNA-like” to elicit RNase H activity. In certain embodiments, one or more non-DNA-like nucleoside in the gap of a gapmer is tolerated.

In certain antisense activities, an antisense compound or a portion of an antisense compound is loaded into an RNA-induced silencing complex (RISC), ultimately resulting in cleavage of the target nucleic acid. For example, certain antisense compounds result in cleavage of the target nucleic acid by Argonaute. Antisense compounds that are loaded into RISC are RNAi compounds. RNAi compounds may be double-stranded (siRNA) or single-stranded (ssRNA).

In certain embodiments, hybridization of an antisense compound to a target nucleic acid does not result in recruitment of a protein that cleaves that target nucleic acid. In certain embodiments, hybridization of the antisense compound to the target nucleic acid results in alteration of splicing of the target nucleic acid. In certain embodiments, hybridization of an antisense compound to a target nucleic acid results in inhibition of a binding interaction between the target nucleic acid and a protein or other nucleic acid. In certain embodiments, hybridization of an antisense compound to a target nucleic acid results in alteration of translation of the target nucleic acid.

Antisense activities may be observed directly or indirectly. In certain embodiments, observation or detection of an antisense activity involves observation or detection of a change in an amount of a target nucleic acid or protein encoded by such target nucleic acid, a change in the ratio of splice variants of a nucleic acid or protein and/or a phenotypic change in a cell or animal.

V. Certain Target Nucleic Acids

In certain embodiments, oligomeric compounds comprise or consist of an oligonucleotide comprising a region that is complementary to a target nucleic acid. In certain embodiments, the target nucleic acid is an endogenous RNA molecule. In certain embodiments, the target nucleic acid encodes a protein. In certain such embodiments, the target nucleic acid is selected from: a mature mRNA and a pre-mRNA, including intronic, exonic and untranslated regions. In certain embodiments, the target RNA is a mature mRNA. In certain embodiments, the target nucleic acid is a pre-mRNA. In certain such embodiments, the target region is entirely within an intron. In certain embodiments, the target region spans an intron/exon junction. In certain embodiments, the target region is at least 50% within an intron. In certain embodiments, the target nucleic acid is the RNA transcriptional product of a retrogene. In certain embodiments, the target nucleic acid is a non-coding RNA. In certain such embodiments, the target non-coding RNA is selected from: a long non-coding RNA, a short non-coding RNA, an intronic RNA molecule.

A. Complementarity/Mismatches to the Target Nucleic Acid

It is possible to introduce mismatch bases without eliminating activity. For example, Gautschi et al (J. Natl. Cancer Inst. 93:463-471, March 2001) demonstrated the ability of an oligonucleotide having 100% complementarity to the bcl-2 mRNA and having 3 mismatches to the bcl-xL mRNA to reduce the expression of both bcl-2 and bcl-xL in vitro and in vivo. Furthermore, this oligonucleotide demonstrated potent anti-tumor activity in vivo. Maher and Dolnick (Nuc. Acid. Res. 16:3341-3358, 1988) tested a series of tandem 14 nucleobase oligonucleotides, and a 28 and 42 nucleobase oligonucleotides comprised of the sequence of two or three of the tandem oligonucleotides, respectively, for their ability to arrest translation of human DHFR in a rabbit reticulocyte assay. Each of the three 14 nucleobase oligonucleotides alone was able to inhibit translation, albeit at a more modest level than the 28 or 42 nucleobase oligonucleotides.

In certain embodiments, oligonucleotides are complementary to the target nucleic acid over the entire length of the oligonucleotide. In certain embodiments, oligonucleotides are 99%, 95%, 90%, 85%, or 80% complementary to the target nucleic acid. In certain embodiments, oligonucleotides are at least 80% complementary to the target nucleic acid over the entire length of the oligonucleotide and comprise a region that is 100% or fully complementary to a target nucleic acid. In certain embodiments, the region of full complementarity is from 6 to 20, 10 to 18, or 18 to 20 nucleobases in length.

In certain embodiments, oligonucleotides comprise one or more mismatched nucleobases relative to the target nucleic acid. In certain embodiments, antisense activity against the target is reduced by such mismatch, but activity against a non-target is reduced by a greater amount. Thus, in certain embodiments selectivity of the oligonucleotide is improved. In certain embodiments, the mismatch is specifically positioned within an oligonucleotide having a gapmer motif. In certain embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6, 7, or 8 from the 5′-end of the gap region. In certain embodiments, the mismatch is at position 9, 8, 7, 6, 5, 4, 3, 2, 1 from the 3′-end of the gap region. In certain embodiments, the mismatch is at position 1, 2, 3, or 4 from the 5′-end of the wing region. In certain embodiments, the mismatch is at position 4, 3, 2, or 1 from the 3′-end of the wing region.

B. LRRK2

In certain embodiments, oligomeric compounds comprise or consist of an oligonucleotide comprising a region that is complementary to a target nucleic acid, wherein the target nucleic acid is LRRK2. In certain embodiments, LRRK2 nucleic acid has the sequence set forth in SEQ ID NO: 1 (GENBANK Accession No: NM_198578.3) and SEQ ID NO: 2 (GENBANK Accession No: NT_029419.11 truncated from nucleotides 2759000 to 2909000).

In certain embodiments, contacting a cell with an oligomeric compound complementary to SEQ ID NO: 1 or SEQ ID NO: 2 reduces the amount of LRRK2 RNA, and in certain embodiments reduces the amount of LRRK2 protein. In certain embodiments, the oligomeric compound consists of a modified oligonucleotide. In certain embodiments, contacting a cell with an oligomeric compound complementary to SEQ ID NO: 1 or SEQ ID NO: 2 ameliorates one or more symptom or hallmark of a neurodegenerative disease. In certain embodiments, the oligomeric compound consists of a modified oligonucleotide. In certain embodiments, the symptom or hallmark is ataxia, neuropathy, and aggregate formation. In certain embodiments, contacting a cell with a modified oligonucleotide complementary to SEQ ID NO: 1 or SEQ ID NO: 2 results in improved motor function, reduced neuropathy, and reduction in number of aggregates. In certain embodiments, the oligomeric compound consists of a modified oligonucleotide

C. Certain Target Nucleic Acids in Certain Tissues

In certain embodiments, oligomeric compounds comprise or consist of an oligonucleotide comprising a region that is complementary to a target nucleic acid, wherein the target nucleic acid is expressed in a pharmacologically relevant tissue. In certain embodiments, the pharmacologically relevant tissues are the cells and tissues that comprise the central nervous system (CNS). Such tissues include brain tissues, such as, cortex, substantia nigra, striatum, midbrain, and brainstem and spinal cord.

VI. Certain Pharmaceutical Compositions

In certain embodiments, described herein are pharmaceutical compositions comprising one or more oligomeric compounds. In certain embodiments, the one or more oligomeric compounds each consists of a modified oligonucleotide. In certain embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable diluent or carrier. In certain embodiments, a pharmaceutical composition comprises or consists of a sterile saline solution and one or more oligomeric compound. In certain embodiments, the sterile saline is pharmaceutical grade saline. In certain embodiments, a pharmaceutical composition comprises or consists of one or more oligomeric compound and sterile water. In certain embodiments, the sterile water is pharmaceutical grade water. In certain embodiments, a pharmaceutical composition comprises or consists of one or more oligomeric compound and phosphate-buffered saline (PBS). In certain embodiments, the sterile PBS is pharmaceutical grade PBS. In certain embodiments, a pharmaceutical composition comprises or consists of one or more oligomeric compound and artificial cerebrospinal fluid. In certain embodiments, the artificial cerebrospinal fluid is pharmaceutical grade.

In certain embodiments, a pharmaceutical composition comprises a modified oligonucleotide and artificial cerebrospinal fluid. In certain embodiments, a pharmaceutical composition consists of a modified oligonucleotide and artificial cerebrospinal fluid. In certain embodiments, a pharmaceutical composition consists essentially of a modified oligonucleotide and artificial cerebrospinal fluid. In certain embodiments, the artificial cerebrospinal fluid is pharmaceutical grade.

In certain embodiments, pharmaceutical compositions comprise one or more oligomeric compound and one or more excipients. In certain embodiments, excipients are selected from water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone.

In certain embodiments, oligomeric compounds may be admixed with pharmaceutically acceptable active and/or inert substances for the preparation of pharmaceutical compositions or formulations. Compositions and methods for the formulation of pharmaceutical compositions depend on a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.

In certain embodiments, pharmaceutical compositions comprising an oligomeric compound encompass any pharmaceutically acceptable salts of the oligomeric compound, esters of the oligomeric compound, or salts of such esters. In certain embodiments, pharmaceutical compositions comprising oligomeric compounds comprising one or more oligonucleotide, upon administration to an animal, including a human, are capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to pharmaceutically acceptable salts of oligomeric compounds, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts. In certain embodiments, prodrugs comprise one or more conjugate group attached to an oligonucleotide, wherein the conjugate group is cleaved by endogenous nucleases within the body.

Lipid moieties have been used in nucleic acid therapies in a variety of methods. In certain such methods, the nucleic acid, such as an oligomeric compound, is introduced into preformed liposomes or lipoplexes made of mixtures of cationic lipids and neutral lipids. In certain methods, DNA complexes with mono- or poly-cationic lipids are formed without the presence of a neutral lipid. In certain embodiments, a lipid moiety is selected to increase distribution of a pharmaceutical agent to a particular cell or tissue. In certain embodiments, a lipid moiety is selected to increase distribution of a pharmaceutical agent to fat tissue. In certain embodiments, a lipid moiety is selected to increase distribution of a pharmaceutical agent to muscle tissue.

In certain embodiments, pharmaceutical compositions comprise a delivery system. Examples of delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical compositions including those comprising hydrophobic compounds. In certain embodiments, certain organic solvents such as dimethylsulfoxide are used.

In certain embodiments, pharmaceutical compositions comprise one or more tissue-specific delivery molecules designed to deliver the one or more pharmaceutical agents of the present invention to specific tissues or cell types. For example, in certain embodiments, pharmaceutical compositions include liposomes coated with a tissue-specific antibody.

In certain embodiments, pharmaceutical compositions comprise a co-solvent system. Certain of such co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. In certain embodiments, such co-solvent systems are used for hydrophobic compounds. A non-limiting example of such a co-solvent system is the VPD co-solvent system, which is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™ and 65% w/v polyethylene glycol 300. The proportions of such co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics. Furthermore, the identity of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.

In certain embodiments, pharmaceutical compositions are prepared for oral administration. In certain embodiments, pharmaceutical compositions are prepared for buccal administration. In certain embodiments, a pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, intrathecal (IT), intracerebroventricular (ICV), etc.). In certain of such embodiments, a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. In certain embodiments, other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives). In certain embodiments, injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like. Certain pharmaceutical compositions for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers. Certain pharmaceutical compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.

Under certain conditions, certain compounds disclosed herein act as acids. Although such compounds may be drawn or described in protonated (free acid) form, in ionized (anion) form, or ionized and in association with a cation (salt) form, aqueous solutions of such compounds exist in equilibrium among such forms. For example, a phosphate linkage of an oligonucleotide in aqueous solution exists in equilibrium among free acid, anion, and salt forms. Unless otherwise indicated, compounds described herein are intended to include all such forms. Moreover, certain oligonucleotides have several such linkages, each of which is in equilibrium. Thus, oligonucleotides in solution exist in an ensemble of forms at multiple positions all at equilibrium. The term “oligonucleotide” is intended to include all such forms. Drawn structures necessarily depict a single form. Nevertheless, unless otherwise indicated, such drawings are likewise intended to include corresponding forms. Herein, a structure depicting the free acid of a compound followed by the term “or salts thereof” expressly includes all such forms that may be fully or partially protonated/de-protonated/in association with a cation. In certain instances, one or more specific cation is identified.

In certain embodiments, oligomeric compounds disclosed herein are in aqueous solution with sodium. In certain embodiments, oligomeric compounds are in aqueous solution with potassium. In certain embodiments, oligomeric compounds are in articial CSF. In certain embodiments, oligomeric compounds are in PBS. In certain embodiments, oligomeric compounds are in water. In certain such embodiments, the pH of the solution is adjusted with NaOH and/or HCl to achieve a desired pH.

VII. Certain Compositions

1. Compound No: 780241

Compound No: 780241 may be characterized as a 5-10-5 MOE gapmer having a sequence of (from 5′ to 3′) GCTCATATCTAAAGACCGCA (incorporated herein as SEQ ID NO: 222), wherein each of nucleosides 1-5 and 16-20 (from 5′ to 3′) comprise a 2′-MOE modification and each of nucleosides 6-15 are 2′-deoxynucleosides, wherein the internucleoside linkages between nucleosides 2 to 3, 3 to 4, 4 to 5, 16 to 17, and 17 to 18 are phosphodiester internucleoside linkages and the internucleoside linkages between nucleosides 1 to 2, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 18 to 19, and 19 to 20 are phosphorothioate internucleoside linkages, and wherein each cytosine is a 5-methyl cytosine.

Compound No: 780241 may be characterized by the following chemical notation: Ges mCeo Teo mCeo Aes Tds Ads Tds mCds Tds Ads Ads Ads Gds Ads mCeo mCeo Ges mCes Ae; wherein,

A=an adenine nucleobase,

mC=a 5-methyl cytosine nucleobase,

G=a guanine nucleobase,

T=a thymine nucleobase,

e=a 2′-MOE modified sugar,

d=a 2′-deoxyribose sugar,

s=a phosphorothioate internucleoside linkage, and

o=a phosphodiester internucleoside linkage.

Compound No: 780241 may be represented by the following chemical structure:

Compound No: 780241 may be represented by the following chemical structure:

2. Compound No: 802714

Compound No: 802714 may be characterized as a 5-10-5 MOE gapmer, having a sequence of (from 5′ to 3′) TCACCACAAACTCATGGACT (incorporated herein as SEQ ID NO: 888), wherein each of nucleosides 1-5 and 16-20 (from 5′ to 3′) comprise a 2′-MOE modification and each of nucleosides 6-15 are 2′-deoxynucleosides, wherein the internucleoside linkages between nucleosides 2 to 3, 3 to 4, 4 to 5, 16 to 17, and 17 to 18 are phosphodiester internucleoside linkages and the internucleoside linkages between nucleosides 1 to 2, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 18 to 19, and 19 to 20 are phosphorothioate internucleoside linkages, and wherein each cytosine is a 5-methyl cytosine.

Compound No: 802714 may be characterized by the following chemical notation: Tes mCeo Aeo mCeo mCes Ads mCds Ads Ads Ads mCds Tds mCds Ads Tds Geo Geo Aes mCes Te; wherein,

A=an adenine nucleobase,

mC=a 5-methyl cytosine nucleobase,

G=a guanine nucleobase,

T=a thymine nucleobase,

e=a 2′-MOE modified sugar,

d=a 2′-deoxyribose sugar,

s=a phosphorothioate internucleoside linkage, and

o=a phosphodiester internucleoside linkage.

Compound No: 802714 may be represented by the following chemical structure:

Compound No: 802714 may be represented by the following chemical structure:

3. Compound No: 803268

Compound No: 803268 may be characterized as a 5-10-5 MOE gapmer, having a sequence of (from 5′ to 3′) ACCCTTTCCATGTGAACATT (incorporated herein as SEQ ID NO: 1431), wherein each of nucleosides 1-5 and 16-20 (from 5′ to 3′) comprise a 2′-MOE modification and each of nucleosides 6-15 are 2′-deoxynucleosides, wherein the internucleoside linkages between nucleosides 2 to 3, 3 to 4, 4 to 5, 16 to 17, and 17 to 18 are phosphodiester internucleoside linkages and the internucleoside linkages between nucleosides 1 to 2, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 18 to 19, and 19 to 20 are phosphorothioate internucleoside linkages, and wherein each cytosine is a 5-methyl cytosine.

Compound No: 803268 may be characterized by the following chemical notation: Aes mCeo mCeo mCeo Tes Tds Tds mCds mCds Ads Tds Gds Tds Gds Ads Aeo mCeo Aes Tes Te; wherein,

A=an adenine nucleobase,

mC=a 5-methyl cytosine nucleobase,

G=a guanine nucleobase,

T=a thymine nucleobase,

e=a 2′-MOE modified sugar,

d=a 2′-deoxyribose sugar,

s=a phosphorothioate internucleoside linkage, and

o=a phosphodiester internucleoside linkage.

Compound No: 803268 may be represented by the following chemical structure:

Compound No: 803268 may be represented by the following chemical structure:

4. Compound No: 876031

Compound No: 876031 may be characterized as a 5-10-5 MOE gapmer, having a sequence of (from 5′ to 3′) ACGCACTTAACAATATCATA (incorporated herein as SEQ TD NO: 3590), wherein each of nucleosides 1-5 and 16-20 (from 5′ to 3′) comprise a 2′-MOE modification and each of nucleosides 6-15 are 2′-deoxynucleosides, wherein the internucleoside linkages between nucleosides 2 to 3, 3 to 4, 4 to 5, 16 to 17, and 17 to 18 are phosphodiester internucleoside linkages and the internucleoside linkages between nucleosides 1 to 2, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 18 to 19, and 19 to 20 are phosphorothioate internucleoside linkages, and wherein each cytosine is a 5-methyl cytosine.

Compound No: 876031 may be characterized by the following chemical notation: Aes mCeo Geo mCeo Aes mCds Tds Tds Ads Ads mCds Ads Ads Tds Ads Teo mCeo Aes Tes Ae; wherein,

A=an adenine nucleobase,

mC=a 5-methyl cytosine nucleobase,

G=a guanine nucleobase,

T=a thymine nucleobase,

e=a 2′-MOE modified sugar,

d=a 2′-deoxyribose sugar,

s=a phosphorothioate internucleoside linkage, and

o=a phosphodiester internucleoside linkage.

Compound No: 876031 may be represented by the following chemical structure:

Compound No: 876031 may be represented by the following chemical structure:

5. Compound No: 876604

Compound No: 876604 may be characterized as a 5-10-5 MOE gapmer, having a sequence of (from 5′ to 3′) AGCAATCATTGGTAGCATAC (incorporated herein as SEQ ID NO: 3385), wherein each of nucleosides 1-5 and 16-20 (from 5′ to 3′) comprise a 2′-MOE modification and each of nucleosides 6-15 are 2′-deoxynucleosides, wherein the internucleoside linkages between nucleosides 2 to 3, 3 to 4, 4 to 5, 16 to 17, and 17 to 18 are phosphodiester internucleoside linkages and the internucleoside linkages between nucleosides 1 to 2, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 18 to 19, and 19 to 20 are phosphorothioate internucleoside linkages, and wherein each cytosine is a 5-methyl cytosine.

Compound No: 876604 may be characterized by the following chemical notation: Aes Geo mCeo Aeo Aes Tds mCds Ads Tds Tds Gds Gds Tds Ads Gds mCeo Aeo Tes Aes mCe; wherein,

A=an adenine nucleobase,

mC=a 5-methyl cytosine nucleobase,

G=a guanine nucleobase,

T=a thymine nucleobase,

e=a 2′-MOE modified sugar,

d=a 2′-deoxyribose sugar,

s=a phosphorothioate internucleoside linkage, and

o=a phosphodiester internucleoside linkage.

Compound No: 876604 may be represented by the following chemical structure:

Compound No: 876604 may be represented by the following chemical structure:

6. Compound No: 934556

Compound No: 934556 may be characterized as a 5-10-5 MOE gapmer, having a sequence of (from 5′ to 3′) CGCACTTAACAATATCATAT (incorporated herein as SEQ ID NO: 852), wherein each of nucleosides 1-5 and 16-20 (from 5′ to 3′) comprise a 2′-MOE modification and each of nucleosides 6-15 are 2′-deoxynucleosides, wherein the internucleoside linkages between nucleosides 2 to 3 and 17 to 18 are phosphodiester internucleoside linkages and the internucleoside linkages between nucleosides 1 to 2, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 16 to 17, 18 to 19, and 19 to 20 are phosphorothioate internucleoside linkages, and wherein each cytosine is a 5-methyl cytosine.

Compound No: 934556 may be characterized by the following chemical notation: mCes Geo mCes Aes mCes Tds Tds Ads Ads mCds Ads Ads Tds Ads Tds mCes Aeo Tes Aes Te; wherein,

-   -   A=an adenine nucleobase,     -   mC=a 5-methyl cytosine nucleobase,     -   G=a guanine nucleobase,     -   T=a thymine nucleobase,     -   e=a 2′-MOE modified sugar,     -   d=a 2′-deoxyribose sugar,     -   s=a phosphorothioate internucleoside linkage, and     -   o=a phosphodiester internucleoside linkage.

Compound No: 934556 may be represented by the following chemical structure:

Compound No: 934556 may be represented by the following chemical structure:

VIII. Certain Hotspot Regions

1. Nucleobases 18,633-18,658 of SEQ ID NO: 2

In certain embodiments, nucleobases 18,633-18,658 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, siRNAs are complementary to nucleobases 18,633-18,658 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are complementary to nucleobases 18,633-18,658 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: sooosssssssssssooss.

The nucleobase sequences of SEQ ID Nos: 852, 1997, 2073, 2148, 3513, and 3590 are complementary to nucleobases 18,633-18,658 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to nucleobases 18,633-18,658 of SEQ ID NO: 2 achieve at least 54% reduction of LRRK2 RNA in vitro in at least one single dose assay.

2. Nucleobases 21,721-21,755 of SEQ ID NO: 2

In certain embodiments, nucleobases 21,721-21,755 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, siRNAs are complementary to nucleobases 21,721-21,755 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are complementary to nucleobases 21,721-21,755 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: sooosssssssssssooss.

The nucleobase sequences of SEQ ID Nos: 291, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, and 880 are complementary to nucleobases 21,721-21,755 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to nucleobases 21,721-21,755 of SEQ ID NO: 2 achieve at least 52% reduction of LRRK2 RNA in vitro in at least one single dose assay.

3. Nucleobases 27,963-28,016 of SEQ ID NO: 2

In certain embodiments, nucleobases 27,963-28,016 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, siRNAs are complementary to nucleobases 27,963-28,016 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are complementary to nucleobases 27,963-28,016 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: sooosssssssssssooss.

The nucleobase sequences of SEQ ID Nos: 293, 886, 887, 888, 889, 890, 891, 892, 893, and 3745 are complementary to nucleobases 27,963-28,016 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to nucleobases 27,963-28,016 of SEQ ID NO: 2 achieve at least 39% reduction of LRRK2 RNA in vitro in at least one single dose assay.

4. Nucleobases 35,415-35,446 of SEQ ID NO: 2

In certain embodiments, nucleobases 35,415-35,446 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, siRNAs are complementary to nucleobases 35,415-35,446 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are complementary to nucleobases 35,415-35,446 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: sooosssssssssssooss.

The nucleobase sequences of SEQ ID Nos: 920, 921, 2378, 2454, 2530, 2606, 2683, 2759, 2835, 3061, 3137, 3212, and 3288 are complementary to nucleobases 35,415-35,446 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to nucleobases 35,415-35,446 of SEQ ID NO: 2 achieve at least 42% reduction of LRRK2 RNA in vitro in at least one single dose assay.

5. Nucleobases 77,221-77,264 of SEQ ID NO: 2

In certain embodiments, nucleobases 77,221-77,264 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, siRNAs are complementary to nucleobases 77,221-77,264 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are complementary to nucleobases 77,221-77,264 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers.

In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: sooosssssssssssooss.

The nucleobase sequences of SEQ ID Nos: 131, 217, 1106, 1107, and 1108 are complementary to nucleobases 77,221-77,264 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to nucleobases 77,221-77,264 of SEQ ID NO: 2 achieve at least 51% reduction of LRRK2 RNA in vitro in at least one single dose assay.

6. Nucleobases 81,581-81,612 and 87,838-87,869 of SEQ ID NO: 2

In certain embodiments, nucleobases 81,581-81,612 and 87,838-87,869 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, siRNAs are complementary to nucleobases 81,581-81,612 and 87,838-87,869 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are complementary to nucleobases 81,581-81,612 and 87,838-87,869 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: sooosssssssssssooss.

The nucleobase sequences of SEQ ID Nos: 667, 668, 669, 670, 671, 1785, 1786, 1787, 1788, 1789, 1790, 1791, and 1792 are complementary to nucleobases 81,581-81,612 and 87,838-87,869 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to nucleobases 81,581-81,612 and 87,838-87,869 of SEQ ID NO: 2 achieve at least 38% reduction of LRRK2 RNA in vitro in at least one single dose assay.

7. Nucleobases 81,627-81,651 of SEQ ID NO: 2

In certain embodiments, nucleobases 81,627-81,651 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, siRNAs are complementary to nucleobases 81,627-81,651 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are complementary to nucleobases 81,627-81,651 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: sooosssssssssssooss.

The nucleobase sequences of SEQ ID Nos: 674, 1799, 1800, 1801, 1802, and 1803 are complementary to nucleobases 81,627-81,651 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to nucleobases 81,627-81,651 of SEQ ID NO: 2 achieve at least 66% reduction of LRRK2 RNA in vitro in at least one single dose assay.

8. Nucleobases 82,058-82,081 of SEQ ID NO: 2

In certain embodiments, nucleobases 82,058-82,081 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, siRNAs are complementary to nucleobases 82,058-82,081 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are complementary to nucleobases 82,058-82,081 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers.

In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: sooosssssssssssooss.

The nucleobase sequences of SEQ ID Nos: 222, 1130, 1131, 1132, and 1133 are complementary to nucleobases 82,058-82,081 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to nucleobases 82,058-82,081 of SEQ ID NO: 2 achieve at least 53% reduction of LRRK2 RNA in vitro in at least one single dose assay.

9. Nucleobases 82,180-82,220 of SEQ ID NO: 2

In certain embodiments, nucleobases 82,180-82,220 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, siRNAs are complementary to nucleobases 82,180-82,220 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are complementary to nucleobases 82,180-82,220 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: sooosssssssssssooss.

The nucleobase sequences of SEQ ID Nos: 225, 1145, 2005, 2840, 3369, 3446, 3521, 3598, and 3674 are complementary to nucleobases 82,180-82,220 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to nucleobases 82,180-82,220 of SEQ ID NO: 2 achieve at least 64% reduction of LRRK2 RNA in vitro in at least one single dose assay.

10. Nucleobases 82,500-82,525 of SEQ ID NO: 2

In certain embodiments, nucleobases 82,500-82,525 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, siRNAs are complementary to nucleobases 82,500-82,525 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are complementary to nucleobases 82,500-82,525 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: sooosssssssssssooss.

The nucleobase sequences of SEQ ID Nos: 439, 1807, 1808, 1809, 1810, 1811, and 1812 are complementary to nucleobases 82,500-82,525 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to nucleobases 82,500-82,525 of SEQ ID NO: 2 achieve at least 49% reduction of LRRK2 RNA in vitro in at least one single dose assay.

11. Nucleobases 91,038-91,067 of SEQ ID NO: 2

In certain embodiments, nucleobases 91,038-91,067 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, siRNAs are complementary to nucleobases 91,038-91,067 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are complementary to nucleobases 91,038-91,067 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers.

In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: sooosssssssssssooss.

The nucleobase sequences of SEQ ID Nos: 692, 1826, 1827, 1828, 1829, 1830, 1831, 1832, 1833, 1834, and 1835 are complementary to nucleobases 91,038-91,067 of SEQ ID NO: 2.

The modified oligonucleotides of Compound Nos: 780642, 803664, 803665, 803666, 803667, 803668, 803669, 803670, 803671, 803672, and 803673 are complementary to nucleobases 91,038-91,067 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to nucleobases 91,038-91,067 of SEQ ID NO: 2 achieve at least 42% reduction of LRRK2 RNA in vitro in at least one single dose assay.

12. Nucleobases 92,148-92,173 of SEQ ID NO: 2

In certain embodiments, nucleobases 92,148-92,173 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, siRNAs are complementary to nucleobases 92,148-92,173 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are complementary to nucleobases 92,148-92,173 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers.

In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: sooosssssssssssooss.

The nucleobase sequences of SEQ ID Nos: 1213, 2613, 2690, 3143, 3219, and 3295 are complementary to nucleobases 92,148-92,173 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to nucleobases 92,148-92,173 of SEQ ID NO: 2 achieve at least 59% reduction of LRRK2 RNA in vitro in at least one single dose assay.

13. Nucleobases 98,186-98,220 of SEQ ID NO: 2

In certain embodiments, nucleobases 98,186-98,220 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, siRNAs are complementary to nucleobases 98,186-98,220 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are complementary to nucleobases 98,186-98,220 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: sooosssssssssssooss.

The nucleobase sequences of SEQ ID Nos: 1231, 1232, 2462, 2538, 2614, 2691, 2767, 3069, 3144, 3220, 3296 are complementary to nucleobases 98,186-98,220 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to nucleobases 98,186-98,220 of SEQ ID NO: 2 achieve at least 55% reduction of LRRK2 RNA in vitro in at least one single dose assay.

14. Nucleobases 98,218-98,242 of SEQ ID NO: 2

In certain embodiments, nucleobases 98,218-98,242 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, siRNAs are complementary to nucleobases 98,218-98,242 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are complementary to nucleobases 98,218-98,242 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: sooosssssssssssooss.

The nucleobase sequences of SEQ ID Nos: 150, 1233, 2008, 3372, 3449, and 3524 are complementary to nucleobases 98,218-98,242 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to nucleobases 98,218-98,242 of SEQ ID NO: 2 achieve at least 38% reduction of LRRK2 RNA in vitro in at least one single dose assay.

15. Nucleobases 99,199-99,223 of SEQ ID NO: 2

In certain embodiments, nucleobases 99,199-99,223 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, siRNAs are complementary to nucleobases 99,199-99,223 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are complementary to nucleobases 99,199-99,223 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers.

In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: sooosssssssssssooss.

The nucleobase sequences of SEQ ID Nos: 1243, 2311, 2387, 2920, 2995, and 3755 are complementary to nucleobases 99,199-99,223 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to nucleobases 99,199-99,223 of SEQ ID NO: 2 achieve at least 52% reduction of LRRK2 RNA in vitro in at least one single dose assay.

16. Nucleobases 119,903-119,936 of SEQ ID NO: 2

In certain embodiments, nucleobases 119,903-119,936 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, siRNAs are complementary to nucleobases 119,903-119,936 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are complementary to nucleobases 119,903-119,936 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: sooosssssssssssooss.

The nucleobase sequences of SEQ ID Nos: 750, 1927, 1928, 1929, 1930, 1931, 1932, 1933, 1934, 1935, 2822, 2898, 3351, and 3733 are complementary to nucleobases 119,903-119,936 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary to nucleobases 119,903-119,936 of SEQ ID NO: 2 achieve at least 51% reduction of LRRK2 RNA in vitro in at least one single dose assay.

17. Nucleobases 4,062-4,086 of SEQ ID NO: 1

In certain embodiments, nucleobases 4,062-4,086 of SEQ ID NO: 1 comprise a hotspot region. In certain embodiments, siRNAs are complementary to nucleobases 4,062-4,086 of SEQ ID NO: 1. In certain embodiments, modified oligonucleotides are complementary to nucleobases 4,062-4,086 of SEQ ID NO: 1. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: sooosssssssssssooss.

The nucleobase sequences of SEQ ID Nos: 39, 231, 232, 233, 1161, and 1162 are complementary to nucleobases 4,062-4,086 of SEQ ID NO: 1.

In certain embodiments, modified oligonucleotides complementary to nucleobases 4,062-4,086 of SEQ ID NO: 1 achieve at least 56% reduction of LRRK2 RNA in vitro in at least one single dose assay.

Nonlimiting Disclosure and Incorporation by Reference

Each of the literature and patent publications listed herein is incorporated by reference in its entirety.

While certain compounds, compositions and methods described herein have been described with specificity in accordance with certain embodiments, the following examples serve only to illustrate the compounds described herein and are not intended to limit the same. Each of the references, GenBank accession numbers, and the like recited in the present application is incorporated herein by reference in its entirety.

Although the sequence listing accompanying this filing identifies each sequence as either “RNA” or “DNA” as required, in reality, those sequences may be modified with any combination of chemical modifications. One of skill in the art will readily appreciate that such designation as “RNA” or “DNA” to describe modified oligonucleotides is, in certain instances, arbitrary. For example, an oligonucleotide comprising a nucleoside comprising a 2′-OH sugar moiety and a thymine base could be described as a DNA having a modified sugar (2′-OH in place of one 2′-H of DNA) or as an RNA having a modified base (thymine (methylated uracil) in place of a uracil of RNA). Accordingly, nucleic acid sequences provided herein, including, but not limited to those in the sequence listing, are intended to encompass nucleic acids containing any combination of natural or modified RNA and/or DNA, including, but not limited to such nucleic acids having modified nucleobases. By way of further example and without limitation, an oligomeric compound having the nucleobase sequence “ATCGATCG” encompasses any oligomeric compounds having such nucleobase sequence, whether modified or unmodified, including, but not limited to, such compounds comprising RNA bases, such as those having sequence “AUCGAUCG” and those having some DNA bases and some RNA bases such as “AUCGATCG” and oligomeric compounds having other modified nucleobases, such as “AT^(m)CGAUCG,” wherein mC indicates a cytosine base comprising a methyl group at the 5-position.

Certain compounds described herein (e.g., modified oligonucleotides) have one or more asymmetric center and thus give rise to enantiomers, diastereomers, and other stereoisomeric configurations that may be defined, in terms of absolute stereochemistry, as (R) or (S), as a or such as for sugar anomers, or as (D) or (L), such as for amino acids, etc. Compounds provided herein that are drawn or described as having certain stereoisomeric configurations include only the indicated compounds. Compounds provided herein that are drawn or described with undefined stereochemistry include all such possible isomers, including their stereorandom and optically pure forms, unless specified otherwise. Likewise, tautomeric forms of the compounds herein are also included unless otherwise indicated. Unless otherwise indicated, compounds described herein are intended to include corresponding salt forms.

The compounds described herein include variations in which one or more atoms are replaced with a non-radioactive isotope or radioactive isotope of the indicated element. For example, compounds herein that comprise hydrogen atoms encompass all possible deuterium substitutions for each of the ¹H hydrogen atoms. Isotopic substitutions encompassed by the compounds herein include but are not limited to: ²H or ³H in place of 41, ¹³C or ¹⁴C in place of ¹²C, ¹⁵N in place of ¹⁴N, ¹⁷O or ¹⁸O in place of ¹⁶O, and ³³S, ³⁴S, ³⁵S, or ³⁶S in place of ³²S. In certain embodiments, non-radioactive isotopic substitutions may impart new properties on the oligomeric compound that are beneficial for use as a therapeutic or research tool. In certain embodiments, radioactive isotopic substitutions may make the compound suitable for research or diagnostic purposes such as imaging.

EXAMPLES

The following examples illustrate certain embodiments of the present disclosure and are not limiting. Moreover, where specific embodiments are provided, the inventors have contemplated generic application of those specific embodiments. For example, disclosure of an oligonucleotide having a particular motif provides reasonable support for additional oligonucleotides having the same or similar motif. And, for example, where a particular high-affinity modification appears at a particular position, other high-affinity modifications at the same position are considered suitable, unless otherwise indicated.

Example 1: Effect of 5-10-5 MOE Gapmers with Phosphorothioate Internucleoside Linkages on Human LRRK2 RNA Expression In Vitro, Single Dose

Modified oligonucleotides complementary to a human LRRK2 nucleic acid were designed and tested for their effect on LRRK2 RNA in vitro.

Cultured SH-SY5Y cells at a density of 20,000 cells per well were transfected using electroporation with 5,000 nM concentration of modified oligonucleotide or no modified oligonucleotide for untreated controls. After approximately 24 hours, RNA was isolated from the cells and LRRK2 RNA levels were measured by quantitative real-time PCR Human primer probe set RTS3133_MGB (forward sequence TTCCACACTTGCGGTCTTTAGA, designated herein as SEQ ID NO: 11; reverse sequence GCGGGACCTGGTAGGTACTG, designated herein as SEQ ID NO: 12; probe sequence ATGAGCAGCAATGAT, designated herein as SEQ ID: 13) was used to measure RNA levels. LRRK2 RNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented in the table below as percent LRRK2 RNA levels relative to untreated control cells. The modified oligonucleotides with percent control values marked with an asterisk (*) target the amplicon region of the primer probe set. Additional assays may be used to measure the potency and efficacy of oligonucleotides targeting the amplicon region.

The modified oligonucleotides on Table 1 are 5-10-5 MOE gapmers. The gapmers are 20 nucleobases in length, wherein the central gap segment comprises ten 2′-deoxynucleosides and is flanked by wing segments on both the 5′ end and on the 3′ end comprising five 2′-MOE nucleosides. The sugar motif for the gapmers is (from 5′ to 3′): eeeeeddddddddddeeeee; wherein ‘d’ represents a 2′-deoxyribose sugar and ‘e’ represents a 2′-MOE modified sugar. Each internucleoside linkage is a phosphorothioate internucleoside linkage and each cytosine residue is a 5-methyl cytosine. “Start Site” indicates the 5′-most nucleoside to which the gapmer is complementary in the human nucleic acid sequence. “Stop Site” indicates the 3′-most nucleoside to which the gapmer is complementary in the human nucleic acid sequence.

Each modified oligonucleotide listed in Table 1 below is complementary to human LRRK2 nucleic acid sequences SEQ ID NO: 1 or SEQ ID NO: 2, as indicated. ‘N/A’ indicates that the modified oligonucleotide is not complementary to that particular nucleic acid sequence with 100% complementarity. As shown below, modified oligonucleotides complementary to the sequence of human LRRK2 RNA reduced the amount of human LRRK2 RNA.

TABLE 1 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with phosphorothioate internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence control NO 422420 368 387 10392 10411 ATTAATTTGCACAGAAGTGA 75 30 422421 375 394 10399 10418 GACTTCTATTAATTTGCACA 65 31 422425 441 460 10465 10484 ACCAAGGACTTCCCAATCAT 111 32 422428 606 625 16126 16145 GTGCATGGCATCAAAAATTA 35 33 422433 1791 1810 52705 52724 TCCACATTTCTGAATCCCAG 24 34 422435 1904 1923 N/A N/A TCTTGGTCATCTGGATACAT 76 35 422436 1913 1932 N/A N/A CACTGAATTTCTTGGTCATC 84 36 422437 1919 1938 N/A N/A CCCAGACACTGAATTTCTTG 53 37 422450 3886 3905 N/A N/A GAGGAATCTCTTTCAGTTTA 58 38 422451 4064 4083 84059 84078 AACCTTATGATGTCTTTGGC 44 39 422456 4472 4491 88573 88592 GAAACATCCAAATGTGTGCC 64 40 422457 4484 4503 88585 88604 TGCTTCTCATCAGAAACATC 66 41 422458 4580 4599 88681 88700 TCCTCGGTGGCATTCACAAA 96 42 422461 4908 4927 93369 93388 CCACTTGGGTTCCACAAAGT 39 43 422462 4915 4934 93376 93395 TACAAAGCCACTTGGGTTCC 57 44 422466 5480 5499 100469 100488 GGAAACCATTCTTCCATGAG 85 45 422469 5702 5721 101340 101359 TTTCTAGGCAGGTCAGCCAA 74 46 422470 5978 5997 113175 113194 AGCAGGCGATCCAAGGAACC 90 47 422472 6139 6158 118472 118491 CAATGATGGCAGCATTGGGA 72 48 422475 6260 6279 124891 124910 TGTTGGTTATAAATGACATT 81 49 422477 6461 6480 126577 126596 TGAGGATTTTCTTTCAAACA 96 50 422479 6500 6519 129645 129664 TTCAAAATGTCAAAGACCTG 98 51 422480 6841 6860 132551 132570 AAGTGACAGAATCAGTCATC 83 52 422483 7108 7127 137512 137531 TGAGTTTCTGAATGGTGAAA 92 53 438386 117 136 3236 3255 GCTGCCACTAGCCATGGTGG 99 54 438387 185 204 3304 3323 TCCTGGACATTGTTCAGCCT 48 55 438388 381 400 10405 10424 TGGACAGACTTCTATTAATT 73 56 438401 3944 3963 83939 83958 AGTTCCAAGTTGTAACTGAC 71 57 438405 4408 4427 87312 87331 AGAGCCAAGGCTTCATGGCA 98 58 438408 4619 4638 88720 88739 TTTATGATGGTTTTCCGAAG 107 59 438410 4649 4668 N/A N/A TGATCTCGGATCTTGAAATT 88 60 438429 8882 8901 147051 147070 ATGAATACTGGTCAGGGCCA 77 61 438432 N/A N/A 4483 4502 AAACTGATTTCAGTTCCCCA 50 62 438433 N/A N/A 52819 52838 ACCTTGGTCATCTGGATACA 93 63 438434 N/A N/A 92072 92091 TGATCTCGGATCTATGAAAT 94 64 438436 N/A N/A 114858 114877 CCCCTGGTGTTCAAAAGCAG 69 65 438437 N/A N/A 129638 129657 TGTCAAAGACCTGAGAAAGT 116 66 438538 171 190 3290 3309 CAGCCTGACTATCAACTTCT 35 67 438539 436 455 10460 10479 GGACTTCCCAATCATTTCCA 90 68 438540 1074 1093 N/A N/A GAAAATAGTCTCAGTGAGGA 70 69 438541 1078 1097 N/A N/A TTAAGAAAATAGTCTCAGTG 98 70 438542 2275 2294 56283 56302 CCATGATGCTGTTATTCTGA 54 71 438543 2282 2301 56290 56309 CATTCAACCATGATGCTGTT 50 72 438544 2361 2380 61982 62001 GCTCTCTTTCTCACATACCT 22 73 438545 2366 2385 61987 62006 GGACTGCTCTCTTTCTCACA 26 74 438546 2525 2544 62146 62165 AATCCTCCAAGGCAAATGCT 55 75 438547 2564 2583 62185 62204 AAAGGACCAAGCCAAGAAGG 58 76 438548 2571 2590 62192 62211 TGGAAATAAAGGACCAAGCC 27 77 438549 2759 2778 65597 65616 ACACTGTCCATAGAAGAGTC 56 78 438550 2764 2783 65602 65621 CAAACACACTGTCCATAGAA 44 79 438551 3503 3522 77252 77271 AAAATCTTCAGTTCCTTCAG 82 80 438552 3857 3876 82202 82221 AGATGCAGTTTCTCTACTCT 67 81 438553 4300 4319 N/A N/A CCTCACGACCTGCAAAATCC 65 82 438554 4305 4324 N/A N/A GAATTCCTCACGACCTGCAA 77 83 438555 4480 4499 88581 88600 TCTCATCAGAAACATCCAAA 77 84 438556 4575 4594 88676 88695 GGTGGCATTCACAAAGTGGT 52 85 438557 4641 4660 N/A N/A GATCTTGAAATTAAGGCTCT 69 86 438558 5225 5244 99231 99250 AATCTTGACCAAAATCCCAT 79 87 438559 5530 5549 100519 100538 TCTTCAACAGAGTTTCTCCT 81 88 438560 5537 5556 100526 100545 GCCCATTTCTTCAACAGAGT 30 89 438561 5568 5587 100557 100576 ATGTTCTTCACCATCATTAA 98 90 438562 5735 5754 101373 101392 TCAAATTCCAACTCATCATT 111 91 438563 5825 5844 106516 106535 AAAATCTTCACAGCCACTTC 109 92 438564 5829 5848 106520 106539 ATTAAAAATCTTCACAGCCA 136 93 438565 6000 6019 113197 113216 GAGGCTGGCTTTGTCCTGCT 52 94 438566 6074 6093 118407 118426 ATAATCATGGCTGAGTGGAG 83 95 438567 6135 6154 118468 118487 GATGGCAGCATTGGGATACA 90 96 438568 6401 6420 126517 126536 CCATATTCTTTAACTGGATC 74 97 438569 6427 6446 126543 126562 TCTCAACCATAGGCCATGGG 47 98 438570 6465 6484 126581 126600 TTCTTGAGGATTTTCTTTCA 106 99 438571 6494 6513 N/A N/A ATGTCAAAGACCTGGGCAGA 107 100 438572 6572 6591 129717 129736 GCAACCATGCATTCAACAAT 76 101 438573 6696 6715 132406 132425 TCTACTATCAGCAACTTCCT 89 102 438574 6845 6864 132555 132574 AAACAAGTGACAGAATCAGT 110 103 438575 7632 7651 145801 145820 GTGTTTTTCTAAATTTTGCA 65 104 438576 7640 7659 145809 145828 ACTTCAATGTGTTTTTCTAA 105 105 438577 N/A N/A 3658 3677 AAATAACTTGGAGGCTGGAA 114 106 438578 N/A N/A 4487 4506 GACAAAACTGATTTCAGTTC 82 107 438579 N/A N/A 77354 77373 CACTTACCAAGAAAATTCAT 118 108 438580 N/A N/A 116733 116752 ATTATAGAATTTAATCTTAA 96 109 438581 N/A N/A 142937 142956 ACCTCCCTAGAACCATAAAG 104 110 438582 60 79 3179 3198 TCCGCTGCTCAGGGAACCGG 65 111 438583 449 468 10473 10492 TGGTGAACACCAAGGACTTC 55 112 438584 457 476 N/A N/A GAATCAATTGGTGAACACCA 63 113 438585 529 548 13795 13814 GGAGGAGATCTAAGGTCTTC 90 114 438586 550 569 N/A N/A AGGTGATTTTACCTGAAGTT 64 115 438587 624 643 16144 16163 ATCATTGGCTGGAAATGAGT 51 116 438588 883 902 21714 21733 GGAATGCTTTCATAGCTTCC 56 117 438589 1166 1185 29427 29446 TTGTAACAGGCTTCCAGCCA 53 118 438590 1300 1319 N/A N/A CCCTATGAGCTGGGAAATGG 79 119 438591 1534 1553 N/A N/A CCAGGGAAGTGTTGCTTCCT 77 120 438592 1610 1629 37659 37678 TCCAGCTGCACTGGTAATGA 90 121 438593 1774 1793 N/A N/A CAGGATTTCCAATGAACCTG 72 122 438594 1885 1904 52799 52818 TCTGCAGTGTGTGAAGCACT 76 123 438595 2108 2127 56042 56061 TGATGCACCAGCAGCTTAGA 48 124 438596 2318 2337 56326 56345 TTTGCTTGATTGGCATCTGC 55 125 438597 2380 2399 62001 62020 GTTCCACCAATTTGGGACTG 34 126 438598 2412 2431 62033 62052 ATCTTGTTCACGAGATCCAC 70 127 438599 2515 2534 62136 62155 GGCAAATGCTATTGTTGGCC 63 128 438600 3171 3190 73707 73726 GAGTGCATTCTGGTGAAGCT 70 129 438601 3211 3230 N/A N/A AACTCTTCAGAGTTTCACAT 94 130 438602 3475 3494 77224 77243 GGGAGCATATCCCTGATATT 42 131 438603 3565 3584 77314 77333 CTTTAGGACAAGCCTCAAGA 71 132 438604 3702 3721 N/A N/A AGACCGCAAGTGTGGAAGAT 17* 133 438605 3707 3726 N/A N/A TCTAAAGACCGCAAGTGTGG 22* 134 438606 3930 3949 83925 83944 ACTGACATCCAGAGATGTCA 126 135 438607 3952 3971 83947 83966 AGGATCTTAGTTCCAAGTTG 95 136 438608 3957 3976 83952 83971 GGGAAAGGATCTTAGTTCCA 70 137 438609 3969 3988 83964 83983 CCCCATTTCATTGGGAAAGG 77 138 438610 4190 4209 86685 86704 CCAAGATCTGATTTCTTGGT 104 139 438611 4353 4372 87257 87276 AGCAAGGTACAATGCTCGCT 69 140 438612 4395 4414 87299 87318 CATGGCATCAACTTCAGCCT 83 141 438613 4413 4432 87317 87336 ATTGAAGAGCCAAGGCTTCA 94 142 438614 4422 4441 N/A N/A AGCCTTTATATTGAAGAGCC 103 143 438615 4428 4447 N/A N/A AGCGCGAGCCTTTATATTGA 91 144 438616 4433 4452 N/A N/A GAAGAAGCGCGAGCCTTTAT 66 145 438617 4544 4563 88645 88664 GCAGGGAACCCTCGCTTATT 97 146 438618 4682 4701 92105 92124 TAGCAGTCTGGAATCAGCTG 89 147 438619 4816 4835 92239 92258 CGTGAGGAAGCTCATTTTCA 70 148 438620 4963 4982 98111 98130 GTTTTGGACAACCTTCCACT 96 149 438621 5074 5093 98222 98241 TCTGGAATTTTTCTAGGAGC 62 150 438622 5116 5135 98264 98283 TGCTTGGAACCAGCAAATAT 78 151 438623 5451 5470 100440 100459 GTGGTCCACAACTTGGCCCA 71 152 438624 5745 5764 101383 101402 TGGAGCTTGTTCAAATTCCA 104 153 438625 5887 5906 113084 113103 GGTGGAGGTGGCAAAGCACC 78 154 438626 5968 5987 113165 113184 CCAAGGAACCCTTGGAGGCT 97 155 438627 5986 6005 113183 113202 CCTGCTGAAGCAGGCGATCC 75 156 438628 5991 6010 113188 113207 TTTGTCCTGCTGAAGCAGGC 89 157 438629 6058 6077 N/A N/A GGAGGTATCTCAAACCATCA 111 158 438630 6149 6168 118482 118501 GCAATCTTTGCAATGATGGC 72 159 438631 6157 6176 118490 118509 CGTAGTCAGCAATCTTTGCA 78 160 438632 6581 6600 129726 129745 TGATGTGTAGCAACCATGCA 62 161 438633 6586 6605 129731 129750 TGTTGTGATGTGTAGCAACC 77 162 438634 6613 6632 129758 129777 AGCCCAGCCAAATGCTTGCA 97 163 438635 6624 6643 129769 129788 GGTGTGCCCACAGCCCAGCC 70 164 438636 6677 6696 129822 129841 TCAGAAGTGTATCCTTCAGT 95 165 438637 7373 7392 143021 143040 GCAGTGTTCTTCTGAAGGCA 100 166 438638 7482 7501 143130 143149 TGTCATCATGACTCTGACCG 74 167 438639 8333 8352 146502 146521 AGGACTTTGACAGTATGTCA 66 168 438640 8696 8715 146865 146884 TCCTTCAGCAACTGAAAAGT 85 169 438641 8748 8767 146917 146936 TGGAAGCCTAGGGTGGCAGA 62 170 438642 8914 8933 147083 147102 AGTTGTCCTATCACAGGGAA 90 171 438643 N/A N/A 78939 78958 ATCAGATTCCCCTGAGGTAC 93 172 438644 N/A N/A 78947 78966 CAGTCTGAATCAGATTCCCC 85 173 438645 N/A N/A 143365 143384 GTTCAGCTGCAGTAATCTGC 67 174 438646 N/A N/A 143372 143391 ACTGAGTGTTCAGCTGCAGT 80 175 438647 N/A N/A 143377 143396 CCCAAACTGAGTGTTCAGCT 99 176 438648 N/A N/A 10479 10498 ACTTACTGGTGAACACCAAG 121 177 438649 N/A N/A 31012 31031 ATGAGCTGGGAAACTTTCAA 84 178 438650 N/A N/A 41888 41907 TCTGGCATGCCTAAATGCAC 101 179 438651 N/A N/A 52827 52846 TTGTACTGACCTTGGTCATC 126 180 438652 N/A N/A 76342 76361 TCTTCAGAGTCTGAAAAGAC 83 181 438653 N/A N/A 88530 88549 AAGCGCGAGCCTGGAGGGAA 89 182 438654 N/A N/A 118392 118411 TGGAGGTATCTGCCAGAAAA 91 183 438655 N/A N/A 118553 118572 ATCACCTACCTGGTGTGCCC 122 184

Example 2: Effect of 5-10-5 MOE Gapmers with Mixed Internucleoside Linkages on Human LRRK2 RNA Expression In Vitro, Single Dose

Modified oligonucleotides complementary to a human LRRK2 nucleic acid were designed and tested for their effect on LRRK2 RNA in vitro. The modified oligonucleotides were tested in a series of experiments that had similar culture conditions.

Cultured SH-SY5Y cells at a density of 20,000 cells per well were transfected using electroporation with 5,000 nM concentration of modified oligonucleotide or no modified oligonucleotide for untreated controls. After approximately 24 hours, RNA was isolated from the cells and LRRK2 RNA levels were measured by quantitative real-time PCR Human primer probe sets RTS3132 (forward sequence CATCACTCAGGCTGTTAAGACAAGA, designated herein as SEQ ID NO: 14; reverse sequence CAGCTGCCAGCAAAGATATCAA, designated herein as SEQ ID NO: 15; probe sequence CTTTGCCACCTCCACCACCCCA, designated herein as SEQ ID: 16), RTS3133_MGB (forward sequence TTCCACACTTGCGGTCTTTAGA, designated herein as SEQ ID NO: 11; reverse sequence GCGGGACCTGGTAGGTACTG, designated herein as SEQ ID NO: 12; probe sequence ATGAGCAGCAATGAT, designated herein as SEQ ID: 13), and RTS3146_MGB (forward sequence GAGCTTCCTCACGCAGTTCAC, designated herein as SEQ ID NO: 17; reverse sequence TGCTGGGTCTTGAAAATGAAGA, designated herein as SEQ ID NO: 18; probe sequence TTCTAAATGAATCAGGAGTCC, designated herein as SEQ ID: 19) were used to measure RNA levels. LRRK2 RNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented in the table below as percent LRRK2 RNA levels relative to untreated control cells. The modified oligonucleotides with percent control values marked with an asterisk (*) target the amplicon region of the primer probe set.

The modified oligonucleotides in Table 2 are 5-10-5 MOE gapmers. The gapmers are 20 nucleobases in length, wherein the central gap segment comprises ten 2′-deoxynucleosides and is flanked by wing segments on both the 5′ end and on the 3′ end comprising five 2′-MOE nucleosides. The sugar motif for the gapmers is (from 5′ to 3′): eeeeeddddddddddeeeee; wherein ‘d’ represents a 2′-deoxyribose sugar and ‘e’ represents a 2′-MOE modified sugar. All cytosine residues throughout each gapmer are 5-methyl cytosines. The internucleoside linkages for each gapmer are mixed phosphodiester and phosphorothioate linkages. The internucleoside linkage motif for the gapmers is (from 5′ to 3′): sooosssssssssssooss; wherein ‘o’ represents a phosphodiester internucleoside linkage and ‘s’ represents a phosphorothioate internucleoside linkage. “Start Site” indicates the 5′-most nucleoside to which the gapmer is complementary in the human nucleic acid sequence. “Stop Site” indicates the 3′-most nucleoside to which the gapmer is complementary in the human nucleic acid sequence.

Each modified oligonucleotide listed in Table 2 below is complementary to human LRRK2 nucleic acid sequences SEQ ID NO: 1 or SEQ ID NO: 2, as indicated. ‘N/A’ indicates that the modified oligonucleotide is not complementary to that particular nucleic acid sequence with 100% complementarity. As shown below, modified oligonucleotides complementary to the sequence of human LRRK2 RNA reduced the amount of human LRRK2 RNA.

TABLE 2 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ LRRK2 LRRK2 ID ID ID ID LRRK2 % % NO: 1 NO: 1 NO: 2 NO: 2 % control control SEQ Compound Start Stop Start Stop control RTS3133 RTS3146 ID Number Site Site Site Site Sequence (5′ to 3′) RTS3132 _MGB _MGB NO 693423 4064 4083 84059 84078 AACCTTATGATGTCTTTGGC 15 31 18 39 693424 4908 4927 93369 93388 CCACTTGGGTTCCACAAAGT 24 31 24 43 693428 2361 2380 61982 62001 GCTCTCTTTCTCACATACCT 10 14 11 73 693429 2571 2590 62192 62211 TGGAAATAAAGGACCAAGCC 26 31 27 77 780202 2368 2387 61989 62008 TGGGACTGCTCTCTTTCTCA 19 26 20 185 780203 2371 2390 61992 62011 ATTTGGGACTGCTCTCTTTC 28 36 32 186 780204 2406 2425 62027 62046 TTCACGAGATCCACTATTCA 48 51 51 187 780205 2451 2470 62072 62091 GTCACCTTTCCCAATGCTTA 21 35 29 188 780206 2499 2518 62120 62139 GGCCACATCCAGGGCCAGCC 56 62 45 189 780207 2543 2562 62164 62183 TCAACTTTTCCTATACAAAA 38 42 47 190 780208 2566 2585 62187 62206 ATAAAGGACCAAGCCAAGAA 53 56 64 191 780209 2569 2588 62190 62209 GAAATAAAGGACCAAGCCAA 48 53 54 192 780210 2573 2592 62194 62213 TCTGGAAATAAAGGACCAAG 21 24 27 193 780211 2576 2595 62197 62216 TTATCTGGAAATAAAGGACC 39 37 41 194 780212 2587 2606 62208 62227 AATTAGAAGTCTTATCTGGA 59 61 59 195 780213 2632 2651 65470 65489 TCACCATTCTTGCTAGTGTA 41 42 50 196 780214 2678 2697 65516 65535 CCTGAGGCTGTTCCTTCTTC 37 47 44 197 780215 2722 2741 65560 65579 CATCAAATTTAGACAGCACA 41 44 48 198 780216 2759 2778 65597 65616 ACACTGTCCATAGAAGAGTC 50 48 45 78 780217 2762 2781 65600 65619 AACACACTGTCCATAGAAGA 41 47 43 199 780218 2764 2783 65602 65621 CAAACACACTGTCCATAGAA 31 39 37 79 780219 2766 2785 65604 65623 AGCAAACACACTGTCCATAG 21 27 24 200 780220 2769 2788 65607 65626 TTGAGCAAACACACTGTCCA 34 37 36 201 780221 2810 2829 71653 71672 AGAAATGAGCCTTCACTTCC 35 49 41 202 780222 2854 2873 71697 71716 GGTAAAATTCTCCTACACTA 37 39 38 203 780223 2898 2917 71741 71760 ATGTCTTTGCAAATTTGGTG 41 46 38 204 780224 2942 2961 72966 72985 TTCAGTAAATCTTCATGATC 55 57 64 205 780225 2986 3005 N/A N/A ATGACCTGAGTGAATCATCT 51 46 55 206 780226 3031 3050 73567 73586 GAGAAGAAATGCTGTCTGAA 54 61 62 207 780227 3075 3094 73611 73630 TGCTGAAAGGTCTAGTGATG 34 37 37 208 780228 3120 3139 73656 73675 TATACAGCATTTCTGGCTTA 61 79 59 209 780229 3164 3183 73700 73719 TTCTGGTGAAGCTCCAGCTT 27 32 29 210 780230 3208 3227 N/A N/A TCTTCAGAGTTTCACATAGC 62 70 61 211 780231 3256 3275 76390 76409 AAGGAAATGATGTAAATTTA 65 70 69 212 780232 3300 3319 76434 76453 AGAGACATCAAGATTAGCAA 24 33 35 213 780233 3344 3363 76478 76497 TTCACTGTAGGATCTAAAAC 46 45 45 214 780234 3389 3408 76523 76542 GACAGCTGGTTATATGACAG 30 31 29 215 780235 3433 3452 76567 76586 GCTCCAGTTTCTCTACCACA 41 40 50 216 780236 3494 3513 77243 77262 AGTTCCTTCAGTCTCAAGGG 16 31 22 217 780237 3538 3557 77287 77306 CTGATAGGGATGAAATGTGG 27 31 28 218 780238 3582 3601 77331 77350 GGCACTGAAACTCTCCACTT 25 37 27 219 780239 3626 3645 80906 80925 ATAGAAGGAGGCAAGAAAGG 47 60 67 220 780240 3670 3689 80950 80969 CTGGAATACAGGAAAATTTG 52 44 51 221 780241 3714 3733 82059 82078 GCTCATATCTAAAGACCGCA 10 3* 13 222 780242 3758 3777 82103 82122 GATTTCCAGTGTGCGGGACC 27 20* 33 223 780243 3802 3821 82147 82166 TGCTGATCTGATTATGGCTA 22 36 33 224 780244 3846 3865 82191 82210 CTCTACTCTAGACCATAAAT 25 32 28 225 780245 3891 3910 N/A N/A CTCAGGAGGAATCTCTTTCA 43 47 51 226 780246 3935 3954 83930 83949 TTGTAACTGACATCCAGAGA 63 75 74 227 780247 3979 3998 83974 83993 TGCTTAATTTCCCCATTTCA 23 41 37 228 780248 4023 4042 84018 84037 ATCAAAGTTAAGATGCAGTT 25 30 29 229 780249 4059 4078 84054 84073 TATGATGTCTTTGGCTTTAC 33 41 36 230 780250 4062 4081 84057 84076 CCTTATGATGTCTTTGGCTT 28 34 31 231 780251 4066 4085 N/A N/A GAAACCTTATGATGTCTTTG 42 39 41 232 780252 4067 4086 N/A N/A AGAAACCTTATGATGTCTTT 34 45 50 233 780253 4069 4088 N/A N/A GAAGAAACCTTATGATGTCT 44 61 47 234 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 17 24 14 235 780255 4155 4174 86650 86669 CAATAAGGTGGTTTTACCAC 35 51 47 236 780256 4199 4218 86694 86713 CTTTGCATTCCAAGATCTGA 30 33 32 237 780257 4243 4262 86738 86757 TTATTTGGATAGGCCAGTCT 34 42 50 238 780258 4287 4306 86782 86801 AAAATCCCACACATTTAGGA 54 60 57 239 780259 4350 4369 87254 87273 AAGGTACAATGCTCGCTGCG 51 65 51 240 780260 4394 4413 87298 87317 ATGGCATCAACTTCAGCCTG 45 41 49 241 780261 4438 4457 88539 88558 GGGAAGAAGAAGCGCGAGCC 29 41 32 242 780262 4483 4502 88584 88603 GCTTCTCATCAGAAACATCC 30 41 35 243 780263 4527 4546 88628 88647 ATTCAGGAGTTCCTTGGTGA 43 85 47 244 780264 4571 4590 88672 88691 GCATTCACAAAGTGGTAATC 35 43 35 245 780265 4615 4634 88716 88735 TGATGGTTTTCCGAAGTTTT 43 46 49 246 780266 4659 4678 92082 92101 AACAACAAGCTGATCTCGGA 49 57 56 247 780267 4703 4722 92126 92145 ATGATTTTTTCAAGTTCTAC 31 47 45 248 780268 4747 4766 92170 92189 CAATTACGGGAAATTCAATT 68 60 57 249 780269 4791 4810 92214 92233 CTGCAGCTGATTTTCTCTCA 23 32 27 250 780270 4835 4854 92258 92277 TCATTTAGAAAGTGAACTGC 40 51 54* 251 780271 4883 4902 93344 93363 TCACTTAACTGCAGTGCTGG 27 38 10* 252 780272 4903 4922 93364 93383 TGGGTTCCACAAAGTACAAG 41 47 42 253 780273 4906 4925 93367 93386 ACTTGGGTTCCACAAAGTAC 42 38 38 254 780274 4910 4929 93371 93390 AGCCACTTGGGTTCCACAAA 28 43 30 255 780275 4913 4932 93374 93393 CAAAGCCACTTGGGTTCCAC 31 43 38 256

Example 3: Effect of 5-10-5 MOE Gapmers with Mixed Internucleoside Linkages on Human LRRK2 RNA Expression In Vitro, Single Dose

Modified oligonucleotides complementary to a human LRRK2 nucleic acid were designed and tested for their effect on LRRK2 RNA in vitro. The modified oligonucleotides were tested in a series of experiments that had similar culture conditions.

Cultured SH-SY5Y cells at a density of 20,000 cells per well were transfected using electroporation with 3,000 nM concentration of modified oligonucleotide or no modified oligonucleotide for untreated controls. After approximately 24 hours, RNA was isolated from the cells and LRRK2 RNA levels were measured by quantitative real-time PCR using human primer probe set RTS3132 as described in Example 2. LRRK2 RNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented in the table below as percent LRRK2 RNA levels relative to untreated control cells. The modified oligonucleotides with percent control values marked with an asterisk (*) target the amplicon region of the primer probe set. Additional assays may be used to measure the potency and efficacy of oligonucleotides targeting the amplicon region.

The modified oligonucleotides in Tables 3-9 are 5-10-5 MOE gapmers. The gapmers are 20 nucleobases in length, wherein the central gap segment comprises ten 2′-deoxynucleosides and is flanked by wing segments on both the 5′ end and on the 3′ end comprising five 2′-MOE nucleosides. The sugar motif for the gapmers is (from 5′ to 3′): eeeeeddddddddddeeeee; wherein ‘d’ represents a 2′-deoxyribose sugar and ‘e’ represents a 2′-MOE modified sugar. All cytosine residues throughout each gapmer are 5-methyl cytosines. The internucleoside linkages for each gapmer are mixed phosphodiester and phosphorothioate linkages. The internucleoside linkage motif for the gapmers is (from 5′ to 3′): sooosssssssssssooss; wherein ‘o’ represents a phosphodiester internucleoside linkage and ‘s’ represents a phosphorothioate internucleoside linkage. “Start Site” indicates the 5′-most nucleoside to which the gapmer is complementary in the human nucleic acid sequence. “Stop Site” indicates the 3′-most nucleoside to which the gapmer is complementary in the human nucleic acid sequence.

Each modified oligonucleotide listed in Tables 3-9 below is complementary to human LRRK2 nucleic acid sequences SEQ ID NO: 1 or SEQ ID NO: 2, as indicated. ‘N/A’ indicates that the modified oligonucleotide is not complementary to that particular nucleic acid sequence with 100% complementarity. As shown below, modified oligonucleotides complementary to the sequence of human LRRK2 RNA reduced the amount of human LRRK2 RNA.

TABLE 3 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′) control NO 690092 171 190 3290 3309 CAGCCTGACTATCAACTTCT 57 67 690093 2366 2385 61987 62006 GGACTGCTCTCTTTCTCACA 70 74 693420 606 625 16126 16145 GTGCATGGCATCAAAAATTA 41 33 693421 1791 1810 52705 52724 TCCACATTTCTGAATCCCAG 48 34 693428 2361 2380 61982 62001 GCTCTCTTTCTCACATACCT 51 73 693438 883 902 21714 21733 GGAATGCTTTCATAGCTTCC 43 117 725607 2362 2381 61983 62002 TGCTCTCTTTCTCACATACC 35 257 725608 2363 2382 61984 62003 CTGCTCTCTTTCTCACATAC 40 258 725609 2364 2383 61985 62004 ACTGCTCTCTTTCTCACATA 62 259 780133 1 20 3120 3139 TCACCGCCCGCAGCCAGCGC 95 260 780134 56 75 3175 3194 CTGCTCAGGGAACCGGCAGG 134 261 780135 100 119 3219 3238 TGGCACCTGCTTCCAACCCG 115 262 780136 157 176 3276 3295 ACTTCTTCAGAGTTTCCTCG 59 263 780137 166 185 3285 3304 TGACTATCAACTTCTTCAGA 86 264 780138 169 188 3288 3307 GCCTGACTATCAACTTCTTC 59 265 780139 173 192 3292 3311 TTCAGCCTGACTATCAACTT 70 266 780140 176 195 3295 3314 TTGTTCAGCCTGACTATCAA 87 267 780141 203 222 3322 3341 GTTTCTATCTGTTTTCCTTC 44 268 780142 271 290 N/A N/A CTTGAAATAACTTGGAGGCG 72 269 780143 315 334 3706 3725 ATAGGAGTCCAAGACGATCA 49 270 780144 362 381 10386 10405 TTGCACAGAAGTGACCAACC 64 271 780145 406 425 10430 10449 GTCCCATTAAGCTTTGCATT 48 272 780146 451 470 N/A N/A ATTGGTGAACACCAAGGACT 48 273 780147 495 514 13761 13780 CAAGTTTACACTGGCATTAT 57 274 780148 539 558 13805 13824 CCTGAAGTTAGGAGGAGATC 32 275 780149 585 604 16105 16124 CATGAAAATATCACTTTCTT 76 276 780150 601 620 16121 16140 TGGCATCAAAAATTAACATG 70 277 780151 604 623 16124 16143 GCATGGCATCAAAAATTAAC 96 278 780152 608 627 16128 16147 GAGTGCATGGCATCAAAAAT 44 279 780153 611 630 16131 16150 AATGAGTGCATGGCATCAAA 74 280 780154 629 648 16149 16168 ACTTCATCATTGGCTGGAAA 57 281 780155 673 692 16193 16212 CTCTCTCAAACAGCACATGT 74 282 780156 717 736 18616 18635 ATAATCTTTGTTCTCAACAA 62 283 780157 764 783 18663 18682 ATTTCCTCTTCATCTTTAAA 134 284 780158 808 827 18707 18726 AAGGAATCGCTAGGGAATGT 57 285 780159 852 871 21683 21702 ATAACACCTGACATTGCCAC 48 286 780160 878 897 21709 21728 GCTTTCATAGCTTCCACCAC 60 287 780161 881 900 21712 21731 AATGCTTTCATAGCTTCCAC 59 288 780162 885 904 21716 21735 AGGGAATGCTTTCATAGCTT 34 289 780163 888 907 21719 21738 CATAGGGAATGCTTTCATAG 99 290 780164 896 915 21727 21746 CTTTCACTCATAGGGAATGC 34 291 780165 940 959 21771 21790 CTAATGTAAGCCTATGGAGC 51 292 780166 988 1007 27963 27982 CCACAAACTCATGGACTTCG 30 293 780167 1032 1051 28007 28026 GATCTGCAATGCTGCATTCT 58 294 780168 1078 1097 N/A N/A TTAAGAAAATAGTCTCAGTG 160 70 780169 1123 1142 29384 29403 CATCATCATTCTCTTGATTC 63 295 780170 1167 1186 29428 29447 TTTGTAACAGGCTTCCAGCC 46 296 780171 1216 1235 N/A N/A AGCATGCGGCCTCCTGCACG 73 297 780172 1260 1279 29611 29630 CTCATGTAAACTGTTTTGGT 62 298 780173 1304 1323 31020 31039 ACTTCCCTATGAGCTGGGAA 134 299 780174 1348 1367 31064 31083 GGAAAACTTCCTTTGATGAA 91 300 780175 1417 1436 35364 35383 TTGATAACAGTATTTTTCTG 75 301 780176 1461 1480 35408 35427 TATATGCTTCTGCATTAACT 78 302 780177 1505 1524 35452 35471 TGATTTAGCATTTTACAGCC 106 303 780178 1549 1568 37598 37617 CTGCTGCCATTATATCCAGG 56 304 780179 1598 1617 37647 37666 GGTAATGATGTCTCATGACG 60 305 780180 1645 1664 37694 37713 CAGGCACTATAAAATGTAAA 93 306 780181 1689 1708 41922 41941 CTTATGATGAAATTCTGTAT 60 307 780182 1734 1753 41967 41986 TTTGTGAATATCATTCTTGA 52 308 780183 1779 1798 52693 52712 AATCCCAGGATTTCCAATGA 78 309 780184 1786 1805 52700 52719 ATTTCTGAATCCCAGGATTT 119 310 780185 1789 1808 52703 52722 CACATTTCTGAATCCCAGGA 41 311 780186 1793 1812 52707 52726 AATCCACATTTCTGAATCCC 70 312 780187 1796 1815 52710 52729 TTTAATCCACATTTCTGAAT 80 313 780188 1826 1845 52740 52759 TCAGGAAAATGTACAATAGA 128 314 780189 1873 1892 52787 52806 GAAGCACTGAATCCATAGCA 34 315 780190 1919 1938 N/A N/A CCCAGACACTGAATTTCTTG 56 37 780191 1963 1982 53003 53022 TGAACACATTCTTCTTTGTA 64 316 780192 2009 2028 53049 53068 TATAAGCTGGAAACCAGAAT 86 317 780193 2053 2072 N/A N/A TCTGAAATCCTTTAGTCTGT 106 318 780194 2097 2116 56031 56050 CAGCTTAGAAAAAGATGCTG 66 319 780195 2141 2160 56075 56094 GACATTTGATGGAATATTAC 45 320 780196 2185 2204 N/A N/A AGAGGTTTAGAAACTGTTGA 44 321 780197 2229 2248 56237 56256 TTTTAAGTAATCATCCATAG 70 322 780198 2273 2292 56281 56300 ATGATGCTGTTATTCTGATC 71 323 780199 2317 2336 56325 56344 TTGCTTGATTGGCATCTGCT 41 324 780200 2356 2375 N/A N/A CTTTCTCACATACCTGACAA 59 325 780201 2359 2378 N/A N/A TCTCTTTCTCACATACCTGA 50 326 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 36 235

TABLE 4 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′) control NO 693428 2361 2380 61982 62001 GCTCTCTTTCTCACATACCT 28 73 693430 5537 5556 100526 100545 GCCCATTTCTTCAACAGAGT 25 89 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 23 235 780276 4929 4948 93390 93409 CTGTGCCATGATTTTACAAA 62 327 780277 4973 4992 98121 98140 CCCTTAGGGTGTTTTGGACA 65 328 780278 5019 5038 98167 98186 CCTTTTTTTTGAAAGAAATT 154 329 780279 5063 5082 98211 98230 TCTAGGAGCTTAAAATACTG 112 330 780280 5109 5128 98257 98276 AACCAGCAAATATTCTTCTC 83 331 780281 5169 5188 99175 99194 TTCAGAGTTCTCACAATGGG 72 332 780282 5217 5236 99223 99242 CCAAAATCCCATTGGAAAAT 88 333 780283 5261 5280 99267 99286 AGCATGTAAGGTGAAATCTC 88 334 780284 5305 5324 100157 100176 GCCAATACATTCTGTTTGGG 25 335 780285 5349 5368 100201 100220 CAGACAATAAGCTTCAGGAG 82 336 780286 5396 5415 100248 100267 ATTTTTAAGAAACTCTCTGG 86 337 780287 5440 5459 100429 100448 CTTGGCCCAAAAGAATACAG 69 338 780288 5488 5507 100477 100496 GCAACCCAGGAAACCATTCT 83 339 780289 5532 5551 100521 100540 tttcttcAAcAGAGtttctc 157 340 780290 5535 5554 100524 100543 CCATTTCTTCAACAGAGTTT 64 341 780291 5539 5558 100528 100547 ATGCCCATTTCTTCAACAGA 59 342 780292 5542 5561 100531 100550 ATAATGCCCATTTCTTCAAC 135 343 780293 5577 5596 100566 100585 GATTTTTTGATGTTCTTCAC 64 344 780294 5622 5641 N/A N/A TAAGAGATCTCCTTCCTCTG 77 345 780295 5666 5685 101304 101323 ATCTGAGATATTGGAATGGT 86 346 780296 5710 5729 101348 101367 ACATAATATTTCTAGGCAGG 48 347 780297 5754 5773 101392 101411 GAGAAACTCTGGAGCTTGTT 138 348 780298 5798 5817 106489 106508 TCATAGGCTGCTCGGTAAAC 109 349 780299 5842 5861 106533 106552 GTGATGTATGTTTATTAAAA 88* 350 780300 5886 5905 113083 113102 GTGGAGGTGGCAAAGCACCA 50* 351 780301 5946 5965 113143 113162 CTCCATCACCAACATCCGGG 121 352 780302 5990 6009 113187 113206 TTGTCCTGCTGAAGCAGGCG 136 353 780303 6034 6053 113231 113250 CGTGGAGTGCAATCCTGTGC 89 354 780304 6078 6097 118411 118430 GTATATAATCATGGCTGAGT 68 355 780305 6122 6141 118455 118474 GGATACAGTGTGAAAAGCAG 61 356 780306 6166 6185 118499 118518 GAGCAATGCCGTAGTCAGCA 61 357 780307 6170 6189 118503 118522 TACTGAGCAATGCCGTAGTC 75 358 780308 6173 6192 118506 118525 CAGTACTGAGCAATGCCGTA 61 359 780309 6175 6194 118508 118527 AGCAGTACTGAGCAATGCCG 58 360 780310 6177 6196 118510 118529 ACAGCAGTACTGAGCAATGC 70 361 780311 6180 6199 118513 118532 TCTACAGCAGTACTGAGCAA 88 362 780312 6211 6230 118544 118563 CTGGTGTGCCCTCTGATGTT 97 363 780313 6255 6274 124886 124905 GTTATAAATGACATTTCCTC 77 364 780314 6299 6318 124930 124949 ATGTCATAGAGTAGTAAACC 111 365 780315 6345 6364 124976 124995 ATTTGGAAACTTCAAACCCT 60 366 780316 6389 6408 N/A N/A ACTGGATCAGGTAATTTTCC 62 367 780317 6433 6452 126549 126568 TTAATTTCTCAACCATAGGC 120 368 780318 6477 6496 126593 126612 AGAAGTAGGCCTTTCTTGAG 95 369 780319 6521 6540 129666 129685 AGACAGACTAATTCAGCTGA 78 370 780320 6568 6587 129713 129732 CCATGCATTCAACAATTACG 57 371 780321 6612 6631 129757 129776 GCCCAGCCAAATGCTTGCAT 41 372 780322 6656 6675 129801 129820 TTTAAGTCAAGAAATGAGAG 92 373 780323 6700 6719 132410 132429 ATATTCTACTATCAGCAACT 97 374 780324 6744 6763 132454 132473 CCAGCTTTCCTTTTCAACAG 132 375 780325 6788 6807 132498 132517 GTATTGATGACCAGGAGAGT 92 376 780326 6832 6851 132542 132561 AATCAGTCATCTTTTCTAGG 98 377 780327 6876 6895 N/A N/A TTTGCTTTGCTTGGAAAAGG 85 378 780328 6920 6939 134252 134271 GCTAACTTGCCATCAGCGGT 84 379 780329 6964 6983 137368 137387 AAGGAGCAGCTCCTTTAAGC 65 380 780330 7008 7027 137412 137431 ACACATCAATGGAGTACTGA 51 381 780331 7052 7071 137456 137475 CCCCACATTACATTTCTTTC 124 382 780332 7096 7115 137500 137519 TGGTGAAATCATTAGAAAAG 119 383 780333 7141 7160 N/A N/A CATAAGAAAACAGTTGGCTT 61 384 780334 7185 7204 141546 141565 AGTGTCTACCACCACTGTTA 124 385 780335 7229 7248 141590 141609 CACACTTCCACAACAGGGCT 116 386 780336 7273 7292 141634 141653 GCACGCAGTCTATTAGTCCA 60 387 780337 7318 7337 142966 142985 GTTTTGATTCCTTGTTTTCT 92 388 780338 7362 7381 143010 143029 CTGAAGGCAGAGGGTTTTCA 78 389 780339 7406 7425 143054 143073 AAAATATGGCCTCCTCCAGT 82 390 780340 7457 7476 143105 143124 CAAAAGTTGTAAATTACACG 77 391 780341 7501 7520 N/A N/A TAAGGCTTCCTAGCTGTGCT 89 392 780342 7545 7564 145148 145167 TTCAGTATTTTTCCGGTTGT 121 393 780343 7589 7608 145758 145777 CAAACGGTCAAGCAAGATTG 138 394 780344 7636 7655 145805 145824 CAATGTGTTTTTCTAAATTT 102 395 780345 7688 7707 145857 145876 TCTTACTCAACAGATGTTCG 92 396 780346 7732 7751 145901 145920 GAGGAGAGAATAATTTTCCT 91 397 780347 7776 7795 145945 145964 GAGTACCCTTTCCATGTGAA 34 398 780348 7822 7841 145991 146010 AAAATAATAACATTCCTTCA 96 399 780349 7867 7886 146036 146055 AAAATACACATTTACTGGTA 115 400 780350 7912 7931 146081 146100 CTGGTATTTATAAGAAATAT 91 401 780351 7960 7979 146129 146148 ATTAGGTACTTCACAGATTT 140 402

TABLE 5 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′) control NO 693428 2361 2380 61982 62001 GCTCTCTTTCTCACATACCT 30 73 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 39 235 780352 8004 8023 146173 146192 AACAAAAAATTATCGGCCTT 79 403 780353 8052 8071 146221 146240 CTTAAGCACAGAATTTAAAA 94 404 780354 8096 8115 146265 146284 ATACCGTGCAGATTTCTAGA 91 405 780355 8140 8159 146309 146328 AAGAAGGAATACATTACATG 148 406 780356 8186 8205 146355 146374 TTTGAATATTTACAAGCATA 163 407 780357 8201 8220 146370 146389 ATTAGTGCAAATTCATTTGA 79 408 780358 8206 8225 146375 146394 ACTTTATTAGTGCAAATTCA 118 409 780359 8211 8230 146380 146399 AAAGGACTTTATTAGTGCAA 48 410 780360 8216 8235 146385 146404 CCAACAAAGGACTTTATTAG 75 411 780361 8221 8240 146390 146409 ACATACCAACAAAGGACTTT 98 412 780362 8231 8250 146400 146419 AAGAGAATTCACATACCAAC 164 413 780363 8275 8294 146444 146463 AATTGAGTGAAGTTGTGTAA 133 414 780364 8319 8338 146488 146507 ATGTCATGTTTTTTCATTAG 157 415 780365 8364 8383 146533 146552 AAAGAGAGTTTCTGTGTCTT 146 416 780366 8408 8427 146577 146596 ACAACTCTATTATGTCTAGG 161 417 780367 8452 8471 146621 146640 TATACAAAATTCAGGGTATC 94 418 780368 8515 8534 146684 146703 TAGTGGTATGAATAAAAAAA 107 419 780369 8561 8580 146730 146749 AGATGAATATAAGCATTAGA 98 420 780370 8605 8624 146774 146793 TATCTGAATGATGTAGGATC 118 421 780371 8650 8669 146819 146838 GTAGGAGCTGTGGAATTCTA 125 422 780372 8694 8713 146863 146882 CTTCAGCAACTGAAAAGTGT 132 423 780373 8741 8760 146910 146929 CTAGGGTGGCAGATATTTTT 126 424 780374 8785 8804 146954 146973 TATTGTGGTAAGCTATGTAA 106 425 780375 8829 8848 146998 147017 AAATGACCTCAAATTATTAC 84 426 780376 8873 8892 147042 147061 GGTCAGGGCCAAAGAATTTA 130 427 780377 8917 8936 147086 147105 ACTAGTTGTCCTATCACAGG 81 428 780378 8962 8981 147131 147150 GTTTTCACATAGTAAAATGC 47 429 780379 9006 9025 147175 147194 TCATCTTTAAGAATTTGATT 94 430 780380 9050 9069 147219 147238 ATAACAAGTTAAAGCATAGC 58 431 780381 9094 9113 147263 147282 CTGGAACAAAGAGCTCTATT 97 432 780382 9143 9162 147312 147331 CTTTGGTAAAAAAAATTGCA 125 433 780383 9183 9202 147352 147371 ATTATTCCATTTAAATATGG 125 434 780384 9188 9207 147357 147376 CCTTTATTATTCCATTTAAA 77 435 780385 9193 9212 147362 147381 AAAAACCTTTATTATTCCAT 93 436 780386 N/A N/A 82225 82244 CCTCTTTCAGTTTATTGTGA 87 437 780387 N/A N/A 82365 82384 ATAGTTGACAGGAATTTATA 71 438 780388 N/A N/A 82505 82524 GTTTAGTGGAAGTATTAAGG 51 439 780389 N/A N/A 82645 82664 TATATGATAACATCACACAT 106 440 780390 N/A N/A 82785 82804 TTCCATAGAACACTCTTTAT 219 441 780391 N/A N/A 82925 82944 AGGAAATTATGCTGTGTTAC 108 442 780392 N/A N/A 83065 83084 AGAAAAATGGTTTATTTAAG 96 443 780394 N/A N/A 79043 79062 ACACTGACCATACACAAGCT 100 444 780395 N/A N/A 143142 143161 GCCTAGCTGTGCTGTCATCA 126 445 780396 N/A N/A 143282 143301 TACCAGTCTTATGTTTCACT 108 446 780397 N/A N/A 143422 143441 ATTTCCCATTTTTGCCTTAG 62 447 780398 N/A N/A 143565 143584 TGTATTGCTGCAAGAAAAAA 90 448 780399 N/A N/A 143705 143724 ACGCAAATATATTTATGCAG 74 449 780400 N/A N/A 143845 143864 ATGTTCAAAACATTCATTAT 137 450 780401 N/A N/A 143985 144004 TAATAGTTTACAGTCATTAA 111 451 780402 N/A N/A 144125 144144 TATAACTTCAGTTATAAGCA 92 452 780403 N/A N/A 144265 144284 AGACAAGCAAGATCTGGTAG 118 453 780404 N/A N/A 144405 144424 ACAGGAGCTAACATTTCAAA 123 454 780405 N/A N/A 144553 144572 AACCGTCTTGGAGTTTATAT 56 455 780406 N/A N/A 144694 144713 TATACTGATACTATGTCAAA 193 456 780407 N/A N/A 144834 144853 CAGTATTTATACATTACCCT 150 457 780408 N/A N/A 144974 144993 TTTTCTAGGTGACCCTTCAA 119 458 780409 N/A N/A 145168 145187 CCTTTCTGCTTTTGTGTACC 93 459 780410 N/A N/A 145310 145329 AAGTTCTTTACACTATAAAC 112 460 780411 N/A N/A 145450 145469 GACATTATGTAGATATAGAT 80 461 780412 N/A N/A 145597 145616 ATTATTATTTATAAAAAACT 124 462 780413 N/A N/A 145740 145759 TGTATCTCTAGAAAAAGAAA 111 463 780414 N/A N/A 3862 3881 AATCACAGTCAGAGGTTCCT 120 464 780415 N/A N/A 4122 4141 CCCTTTTCCAAACTATTCAT 119 465 780416 N/A N/A 4157 4176 GTGACAAAGTTGCATTTTAT 108 466 780417 N/A N/A 4174 4193 TCTACAAGAGTTTGCTAGTG 97 467 780418 N/A N/A 4185 4204 AAGTGCTGAACTCTACAAGA 134 468 780419 N/A N/A 6986 7005 CTCTCACTTCGCTATGACAG 116 469 780420 N/A N/A 7557 7576 AACCGTCAATTTTCTAAAGA 110 470 780421 N/A N/A 7842 7861 CTATTCAATTAAAAGCTTAT 122 471 780422 N/A N/A 8002 8021 CTCAAGGAAAAAACCTGTTT 125 472 780423 N/A N/A 8263 8282 AAAGGCGGCAATTTCTGATA 130 473 780424 N/A N/A 8791 8810 TATACTTGACATGGTCAAAA 177 474 780425 N/A N/A 8820 8839 CTCCAATTCATTCTATTATA 89 475 780426 N/A N/A 11028 11047 AACATAGCTGGTAAAATTAC 143 476 780427 N/A N/A 11977 11996 AAACATTCAATGAATAGAAG 86 477 780428 N/A N/A 12155 12174 ACGGAAGAAATTTTTCTTCA 116 478

TABLE 6 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′) control NO 693428 2361 2380 61982 62001 GCTCTCTTTCTCACATACCT 38 73 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 18 235 780429 N/A N/A 12244 12263 CCAGTCTTCGATTCTCTGCC 135 479 780430 N/A N/A 12353 12372 TTGGCTTTACATTATTGGAA 41 480 780431 N/A N/A 12761 12780 GTGGCCGTTGCTCACGCCTG 130 481 780432 N/A N/A 12910 12929 TCTTAGACATGTTGATATAT 136 482 780433 N/A N/A 14791 14810 TCTTAGCAGGACTGATGAGG 75 483 780434 N/A N/A 15592 15611 CAAATCAATTCATTACCAAG 91 484 780435 N/A N/A 15874 15893 GCTCTAGATCTTTATAAATG 102 485 780436 N/A N/A 16258 16277 TACTTTTCCCAGTATAAGCC 114 486 780437 N/A N/A 16448 16467 CCTTATGCCTTGTTAAGCAA 84 487 780438 N/A N/A 16899 16918 GAAATTAGACTGGTAAACTG 113 488 780439 N/A N/A 16920 16939 ATCCCATTCTGGGAACTGCA 61 489 780440 N/A N/A 17294 17313 TTGTATTCCTTGCAAAATGT 123 490 780441 N/A N/A 17451 17470 TTAGTTGCAAGATAGAACAT 82 491 780442 N/A N/A 17796 17815 ATGGTCTAGTTTCCACAGTA 44 492 780443 N/A N/A 18025 18044 AGTAAGTTCCATTTGGAGTC 61 493 780444 N/A N/A 18279 18298 GGGAAATTCTAGAGAAAACT 64 494 780445 N/A N/A 18439 18458 TGTGAAGCAGCCCTTCCTAA 128 495 780446 N/A N/A 19114 19133 ACTTCAGGTCACACCTTCAT 66 496 780447 N/A N/A 19502 19521 CACATCAAATTAATTTCTTC 95 497 780448 N/A N/A 19553 19572 AAACAGAATATGAACCATTA 129 498 19583 19602 780449 N/A N/A 19556 19575 ACAAAACAGAATATGAACCA 71 499 19586 19605 780450 N/A N/A 19559 19578 AAAACAAAACAGAATATGAA 143 500 19589 19608 780451 N/A N/A 19562 19581 TACAAAACAAAACAGAATAT 190 501 19592 19611 780452 N/A N/A 19953 19972 TGTGGATAAGAAAACATTGT 119 502 780453 N/A N/A 20195 20214 TCTTGACTTTTGCATTATGA 76 503 780454 N/A N/A 20454 20473 AAATGTTAACTGTTCTTTTT 60 504 22583 22602 780455 N/A N/A 20713 20732 TCAGCTATGACCTGTTTCCT 34 505 780456 N/A N/A 20716 20735 AAATCAGCTATGACCTGTTT 128 506 780457 N/A N/A 21493 21512 GTAAAAAATACTATGCTGTT 87 507 780458 N/A N/A 22339 22358 CAAACATTAACAATTTTGCT 118 508 780459 N/A N/A 23396 23415 ACCTCTAATAAATTGTGCTG 73 509 780460 N/A N/A 23640 23659 GCATGGAATAGTAAAGGCCC 61 510 780461 N/A N/A 23970 23989 ATTGCTAGGTAGAGAACTTA 50 511 780462 N/A N/A 24452 24471 TCTAATAAATGACCAAGTTA 76 512 780463 N/A N/A 24633 24652 GAACTTTATATATAGTTATC 92 513 780464 N/A N/A 24916 24935 CTTGTGGGAAAGCATGAATC 67 514 780465 N/A N/A 25082 25101 TCCAACAGTTAACGATCATT 51 515 780466 N/A N/A 25273 25292 GATATAATCATGATACTAGA 57 516 780467 N/A N/A 25433 25452 CAGTTTTAGTCATATAACAA 108 517 780468 N/A N/A 25435 25454 TACAGTTTTAGTCATATAAC 155 518 780469 N/A N/A 25637 25656 ATATGTATATTTATATACAT 171 519 25667 25686 25697 25716 25727 25746 780470 N/A N/A 25640 25659 TAAATATGTATATTTATATA 149 520 25670 25689 25700 25719 25730 25749 25794 25813 25858 25877 780471 N/A N/A 25643 25662 GTATAAATATGTATATTTAT 163 521 25673 25692 25703 25722 25733 25752 25797 25816 25861 25880 780472 N/A N/A 25646 25665 TGTGTATAAATATGTATATT 96 522 25676 25695 25706 25725 25736 25755 25800 25819 25864 25883 780473 N/A N/A 25649 25668 ATCTGTGTATAAATATGTAT 106 523 25679 25698 25709 25728 25739 25758 25803 25822 25867 25886 780474 N/A N/A 25652 25671 TACATCTGTGTATAAATATG 138 524 25682 25701 25712 25731 25742 25761 25806 25825 25870 25889 780475 N/A N/A 25655 25674 ATATACATCTGTGTATAAAT 179 525 25685 25704 25715 25734 25745 25764 25809 25828 25873 25892 780476 N/A N/A 25658 25677 TTTATATACATCTGTGTATA 129 526 25688 25707 25718 25737 25748 25767 25812 25831 25876 25895 780477 N/A N/A 25661 25680 ATATTTATATACATCTGTGT 66 527 25691 25710 25721 25740 25751 25770 25815 25834 25879 25898 780478 N/A N/A 25664 25683 TGTATATTTATATACATCTG 55 528 25694 25713 25724 25743 25754 25773 25818 25837 25882 25901 780479 N/A N/A 25755 25774 TTGTATATTTATATACATCT 88 529 25819 25838 25883 25902 780480 N/A N/A 25758 25777 TATTTGTATATTTATATACA 164 530 25822 25841 25886 25905 780481 N/A N/A 25761 25780 TTATATTTGTATATTTATAT 156 531 25825 25844 25889 25908 780482 N/A N/A 25764 25783 TATTTATATTTGTATATTTA 178 532 25828 25847 25892 25911 780483 N/A N/A 25767 25786 ATATATTTATATTTGTATAT 96 533 25831 25850 25895 25914 780484 N/A N/A 25770 25789 TGTATATATTTATATTTGTA 110 534 25834 25853 25898 25917 780485 N/A N/A 25773 25792 AAATGTATATATTTATATTT 102 535 25837 25856 25901 25920 780486 N/A N/A 25776 25795 TATAAATGTATATATTTATA 144 536 25840 25859 25904 25923 780487 N/A N/A 25779 25798 ATATATAAATGTATATATTT 122 537 25843 25862 25907 25926 780488 N/A N/A 25782 25801 TTTATATATAAATGTATATA 106 538 25846 25865 25910 25929 780489 N/A N/A 25785 25804 ATATTTATATATAAATGTAT 139 539 25849 25868 25913 25932 780490 N/A N/A 25788 25807 TGTATATTTATATATAAATG 98 540 25852 25871 780491 N/A N/A 25791 25810 ATATGTATATTTATATATAA 110 541 25855 25874 780492 N/A N/A 26102 26121 CCATGTTTAGAAGAAATACT 57 542 780493 N/A N/A 26738 26757 ATTACATAGTTTGGCAAAAC 107 543 780494 N/A N/A 27287 27306 ACTGCAGAAATATGTACCTT 89 544 780495 N/A N/A 27387 27406 CACCCCAGGAAGAAGTCCCA 100 545 780496 N/A N/A 27872 27891 GTTAAATTACCTTTAACATA 174 546 780497 N/A N/A 28186 28205 TCCTTGAAAGTATCCTCTAC 90 547 780498 N/A N/A 29148 29167 CCATCCTATCCAGATAAATA 137 548 780499 N/A N/A 29220 29239 AGGTGTGCTTTAGGAGAAGC 34 549 780500 N/A N/A 32958 32977 TTATTAAGGCAGAACTCCAA 92 550 780501 N/A N/A 33224 33243 CATCCCAAGTGCCTACAGAC 146 551 780502 N/A N/A 34124 34143 ACTTTGAAAGTGGCAGAAAA 125 552 780503 N/A N/A 34685 34704 TTACAGTTATTTTCACAAAG 89 553 780504 N/A N/A 34756 34775 CAAACATTATAATTTCTATA 195 554 780505 N/A N/A 34881 34900 TATAAGCATGTGGAGGTATC 90 555

TABLE 7 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′) control NO 693428 2361 2380 61982 62001 GCTCTCTTTCTCACATACCT 49 73 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 33 235 780506 N/A N/A 35751 35770 TGCTATGTGCTATACAATTA 75 556 780507 N/A N/A 36381 36400 CTTACAAGTCTGCAGTTACG 72 557 780508 N/A N/A 36600 36619 TGCCCAGAATCTACAGAATC 99 558 780509 N/A N/A 36661 36680 TCCAGGGCTGCAACTGTACA 107 559 780510 N/A N/A 36909 36928 GTTCTGTGGACACTGAGATA 91 560 780511 N/A N/A 36965 36984 GCTTTGCTTGTTAACTGAAA 66 561 780512 N/A N/A 37065 37084 TTTCTCTCAGGTATTTAAGC 74 562 780513 N/A N/A 37116 37135 GACTTCTTATAAGGTATTTT 65 563 780514 N/A N/A 37198 37217 GGCTGGTACCCAAACTTGTC 91 564 780515 N/A N/A 37201 37220 CAAGGCTGGTACCCAAACTT 72 565 780516 N/A N/A 37303 37322 ACAATCCCAGCAGGTAGGTG 57 566 780517 N/A N/A 37333 37352 ATCCTTCTGACCTACGATGG 72 567 780518 N/A N/A 37398 37417 CTTTGAACTCATAAGATAGA 83 568 780519 N/A N/A 37548 37567 GCTTATTGAAAGACTGATCT 88 569 780520 N/A N/A 38071 38090 GAAGGAAGAGAACAGGTATG 94 570 780521 N/A N/A 38396 38415 CGCCTCTCTCACGCTGCCTG 92 571 780522 N/A N/A 38720 38739 TGCAAACAATTTTAATAAAC 96 572 780523 N/A N/A 38837 38856 TGACTACCATGGACCTCCAA 83 573 780524 N/A N/A 38855 38874 CCTTCACTGGGTCTCACTTG 91 574 780525 N/A N/A 39213 39232 ACTAAGCTGAAACTATGAAT 104 575 780526 N/A N/A 39521 39540 CTGATTGATTGTTAACTAAC 79 576 780527 N/A N/A 40301 40320 TTATAAGTAAGTAGATTTGA 111 577 780528 N/A N/A 40577 40596 AGATTGTTGCACAAATATTT 95 578 780529 N/A N/A 40733 40752 TACTATTCAAATGGATATAA 116 579 780530 N/A N/A 41316 41335 GAACTATGCTAAAAACACTA 90 580 780531 N/A N/A 41593 41612 TTTTGTGTGAGTAGGCTGTG 83 581 780532 N/A N/A 42005 42024 TATATTCAACATACCCTGTT 100 582 780533 N/A N/A 43265 43284 TACAACATAAATTCTTGCCA 57 583 780534 N/A N/A 45337 45356 AATCTTACTGTCAATATAGT 101 584 780535 N/A N/A 45380 45399 TTAAAAGGAAGTAACCATGT 44 585 780536 N/A N/A 45462 45481 TGGTATCCCTCCTAAGTGCT 55 586 780537 N/A N/A 45650 45669 CTCTCTTGGCTCCCGACTGC 75 587 780538 N/A N/A 46047 46066 TACCTTATTTGGAACTCTGC 86 588 780539 N/A N/A 46543 46562 TTACTTATATGTAATTTGTT 77 589 780540 N/A N/A 46567 46586 CATCCTGTAAACCTTTTTTA 79 590 780541 N/A N/A 47702 47721 AAAGATTAAATTAAGCTGCA 121 591 780542 N/A N/A 47812 47831 ACATTAGGAATCTCACCTCA 71 592 780543 N/A N/A 48404 48423 CTGAATATAAATATTATCTA 229 593 780544 N/A N/A 48835 48854 ATGTATAGCTAGAATGAGGA 99 594 780545 N/A N/A 48873 48892 AGATGCAACTCAAGAAAACT 81 595 780546 N/A N/A 48947 48966 TATTTATAAAGCACCTATCT 85 596 50077 50096 780547 N/A N/A 50094 50113 AAATTATATCAAATTGATAT 73 597 780548 N/A N/A 51550 51569 TTTTATAGAGGCTGAGGAGA 98 598 780549 N/A N/A 52154 52173 GCCAAACTTTAAAGATGCAG 33 599 780550 N/A N/A 53367 53386 CGAATAAACTCAGCTAGCTG 87 600 780551 N/A N/A 53543 53562 GACAGTTATTATATATCATG 42 601 780552 N/A N/A 53603 53622 AAATTTATTCTTAATCTCCC 79 602 780553 N/A N/A 54774 54793 AAAACAAGTGAATGCTACAG 92 603 780554 N/A N/A 54886 54905 CTCTTATGATGCTGAGTATC 108 604 780555 N/A N/A 55333 55352 ATGTTTTAATGAAAGATTGG 86 605 780556 N/A N/A 55870 55889 TTAACTATAGATATATTGGG 80 606 780557 N/A N/A 55936 55955 GGCAAAATGAATAAACAGTA 94 607 780558 N/A N/A 56363 56382 TTGAATATTTACCTGACAAA 107 608 780559 N/A N/A 56837 56856 AGTGTTACACAACTTTGGCC 120 609 780560 N/A N/A 56947 56966 GAGGGCTTTAAAGAAAGATA 97 610 780561 N/A N/A 57738 57757 TGTAGTACAGTTGTATCAGG 84 611 780562 N/A N/A 57907 57926 TAAACCTAATACATAATCCT 81 612 780563 N/A N/A 57911 57930 TCTTTAAACCTAATACATAA 102 613 780564 N/A N/A 59330 59349 ATTAGAACCTACTGGACCTT 89 614 780565 N/A N/A 60045 60064 TTTTCTCTAAGATATGCCAT 78 615 780566 N/A N/A 60338 60357 GCTCATAGCAAAATTAAAAG 109 616 780567 N/A N/A 60503 60522 TTTCATTTAATGTAGCACTG 101 617 780568 N/A N/A 61046 61065 AGCAACTGAGACTTGGATTT 91 618 780569 N/A N/A 62829 62848 ACATTTAGTGTGAACAAATG 77 619 780570 N/A N/A 62985 63004 TGCTAGTGAGTGCATCATAA 120 620 780571 N/A N/A 63074 63093 TGGATGGGTACTTTTCTCTA 74 621 780572 N/A N/A 63219 63238 AGGTAGAGAGAGAGTAACAC 92 622 780573 N/A N/A 63229 63248 ATTTAGAGCTAGGTAGAGAG 93 623 780574 N/A N/A 63326 63345 TGAGAAATAAAGTGCTATAG 105 624 780575 N/A N/A 63342 63361 TGAATGGTAGTATATGTGAG 84 625 780576 N/A N/A 63662 63681 ACATTGTGAGGTCAAAAAAG 98 626 780577 N/A N/A 64157 64176 TCCCTCTCCAATGGGCCCAC 74 627 780578 N/A N/A 64433 64452 TTCCAGAGTAATATGTTATG 134 628 780579 N/A N/A 64500 64519 GATAAACCCCAAGAAGGCAA 76 629 780580 N/A N/A 64878 64897 TACATTATGTATTAGCTCTA 76 630 780581 N/A N/A 65152 65171 GTGTTCAAGTCATAGAAATG 88 631 780582 N/A N/A 65840 65859 AACCAATTAGTATAACATTT 75 632

TABLE 8 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′) control NO 693428 2361 2380 61982 62001 GCTCTCTTTCTCACATACCT 39 73 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 30 235 780583 N/A N/A 66279 66298 CTCATTTTTTGCCCTCTCAA 55 633 780584 N/A N/A 66413 66432 TAATTTTCAAAGCGCATGAA 66 634 780585 N/A N/A 66417 66436 ATGTTAATTTTCAAAGCGCA 39 635 780586 N/A N/A 66480 66499 GAAGAAACTTTTTTGGATAA 72 636 780587 N/A N/A 68762 68781 AATAAATTTGGCAACTTATA 126 637 780588 N/A N/A 68885 68904 GAGAAAGTAACACAAACAAT 106 638 780589 N/A N/A 69914 69933 CAAATCCTCAATTACAACTT 91 639 780590 N/A N/A 69919 69938 ACCAACAAATCCTCAATTAC 98 640 780591 N/A N/A 70220 70239 GGAGATAGAGATCAACATTT 55 641 780592 N/A N/A 70279 70298 AATTAAGGGCCATATACATA 79 642 780593 N/A N/A 72795 72814 ACCCAATTATGAGGATAAAA 41 643 780594 N/A N/A 72902 72921 TCATTTATTGGAGAAGAGGA 115 644 780595 N/A N/A 73395 73414 AAACCAAACTATGGAGTTTA 89 645 780596 N/A N/A 75173 75192 AAGTCCTGTCCTCAAAGAGT 74 646 780597 N/A N/A 75176 75195 AACAAGTCCTGTCCTCAAAG 99 647 780598 N/A N/A 75470 75489 AACAAACAAAGTGCCATCTA 52 648 780599 N/A N/A 75646 75665 ATTATAGAGGCTTATTAACC 83 649 780600 N/A N/A 76096 76115 TAGAGTTGAAAGCTTCCTTC 65 650 780601 N/A N/A 76298 76317 CCATCTGAGGAACTTAAGTC 67 651 780602 N/A N/A 76349 76368 GTCAAACTCTTCAGAGTCTG 24 652 780603 N/A N/A 76970 76989 TATATAGTATATATATAATA 138 653 76997 77016 780604 N/A N/A 76973 76992 TTATATATAGTATATATATA 104 654 77000 77019 780605 N/A N/A 76976 76995 GTATTATATATAGTATATAT 106 655 77003 77022 780606 N/A N/A 76979 76998 TAAGTATTATATATAGTATA 105 656 77006 77025 780607 N/A N/A 76982 77001 TAATAAGTATTATATATAGT 76 657 77009 77028 780608 N/A N/A 76985 77004 ATATAATAAGTATTATATAT 78 658 77012 77031 780609 N/A N/A 76988 77007 TATATATAATAAGTATTATA 126 659 77015 77034 780610 N/A N/A 77524 77543 TTTCATAGTTTTATAGCATT 72 660 780611 N/A N/A 77611 77630 GTCTTATAGTTGGGAACGAA 43 661 780612 N/A N/A 78065 78084 ACTATCATTTTAACCTCTGA 71 662 780613 N/A N/A 78080 78099 ACAGTAGGCCAAGTAACTAT 80 663 780614 N/A N/A 78344 78363 AAGTGATGATAATAATTTGC 54 664 780615 N/A N/A 78724 78743 TGGCCAATATTCAGGAGGGT 81 665 780616 N/A N/A 78787 78806 GCTTTGCTTACTAGTGAGTG 70 666 780617 N/A N/A 81581 81600 GTTTGAAGGAATAGCTGACA 60 667 87838 87857 780618 N/A N/A 81584 81603 AGTGTTTGAAGGAATAGCTG 52 668 87841 87860 780619 N/A N/A 81587 81606 CATAGTGTTTGAAGGAATAG 129 669 87844 87863 780620 N/A N/A 81590 81609 AGCCATAGTGTTTGAAGGAA 40 670 87847 87866 780621 N/A N/A 81593 81612 AAAAGCCATAGTGTTTGAAG 91 671 87850 87869 780622 N/A N/A 81596 81615 CTAAAAAGCCATAGTGTTTG 85 672 87853 87872 780623 N/A N/A 81599 81618 ATTCTAAAAAGCCATAGTGT 117 673 87856 87875 780624 N/A N/A 81630 81649 GCAGCATCATGCAAGCAGCA 31 674 87887 87906 780625 N/A N/A 81633 81652 ATTGCAGCATCATGCAAGCA 81 675 87890 87909 780626 N/A N/A 83145 83164 TGGCGGAATGCAGAAATTTA 61 676 780627 N/A N/A 83842 83861 GTGGGAAGGAAGAAATGTGC 70 677 780628 N/A N/A 84184 84203 AGCATATTAATGCCAAATAT 73 678 780629 N/A N/A 84201 84220 AAAGGCAAATGACACACAGC 87 679 780630 N/A N/A 84266 84285 ATTAGTCTGGCTAAGAAGAA 95 680 780631 N/A N/A 84723 84742 ACAGAGCTGAGGTCTGCAAC 58 681 780632 N/A N/A 84951 84970 AAGCTCAGGAGTTCAGAAAA 111 682 780633 N/A N/A 86880 86899 GGTTTCTGGATATTAGAACA 76 683 780634 N/A N/A 87013 87032 TTGTCAGCAACCGATCAAAG 82 684 780635 N/A N/A 88098 88117 CAATTTGGAGTCTACAATGA 78 685 780636 N/A N/A 88353 88372 AAATGTAACCTTACGACATT 77 686 780637 N/A N/A 88867 88886 TAATGCTAACAGCAACAAGG 85 687 780638 N/A N/A 89084 89103 TCACCTTTACCCTTGTGATT 57 688 780639 N/A N/A 89635 89654 CAGGCCAAATAGGACTCTAT 51 689 780640 N/A N/A 89998 90017 AGTCATATTAGTTTCTAATT 96 690 780641 N/A N/A 90808 90827 CTGCTCTGCTAATGGGCTGG 54 691 780642 N/A N/A 91043 91062 TTCATGTATCTCTTAACCCA 42 692 780643 N/A N/A 91084 91103 ACTTCCATATTTACCTGCAA 105 693 780644 N/A N/A 92608 92627 TGCACTAAACTCATTTGACA 98 694 780645 N/A N/A 92700 92719 GCATCATCTCAGGGAGCCAT 45 695 780646 N/A N/A 92957 92976 CAGCATATCTCAGCATACCT 51 696 780647 N/A N/A 93284 93303 CAAACAGTGAAACATGGAAT 89 697 780648 N/A N/A 93697 93716 TTCAATTGACTAATTCAGTA 85 698 780649 N/A N/A 94459 94478 GCTGATTGCAATGTTTCAAT 33 699 780650 N/A N/A 94553 94572 AAATCACATTATCCATGACA 78 700 780651 N/A N/A 95499 95518 AATAGCTGTCAGACAAGTTG 64 701 780652 N/A N/A 95576 95595 TTAGAGCTTCTGCACCATGA 91 702 780653 N/A N/A 95725 95744 TTCCACCTGATTAATTGAAT 70 703 780654 N/A N/A 96460 96479 ATTTTTTAAAGAGTTTGTGC 51 704 780655 N/A N/A 96720 96739 TATAAACTCATAGGCCCTGG 74 705 780656 N/A N/A 97174 97193 GTTTAAGGAATACTTAAACA 81 706 780657 N/A N/A 97323 97342 TGCCCTGAGAATGAAATAAC 73 707 780658 N/A N/A 97591 97610 TTTGATGGATTCTACTTGCA 83 708 780659 N/A N/A 97610 97629 CTCAAAGTAACTACTGCATT 46 709

TABLE 9 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′) control NO 693428 2361 2380 61982 62001 GCTCTCTTTCTCACATACCT 38 73 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 27 235 780660 N/A N/A 99313 99332 TCTAAAAATCTAATAAGTCT 89 710 780661 N/A N/A 99451 99470 TACTCCAAGGTTTTATGAGC 81 711 780662 N/A N/A 99569 99588 AAGAGATAATTACAGTCCCT 71 712 780663 N/A N/A 99813 99832 CTAAACGCAAAACTTTCTGA 107 713 780664 N/A N/A 100778 100797 TAGAATACAAGATTTTATTG 134 714 780665 N/A N/A 102009 102028 TGAGCACCTAAACATGCTAC 65 715 780666 N/A N/A 102270 102289 ACAGCATCGCAGGTCTTGTA 50 716 780667 N/A N/A 102579 102598 AATGCATTTCATAGTTGTCC 60 717 780668 N/A N/A 104248 104267 TTCTCTATTTGAGAATCGCC 64 718 780669 N/A N/A 104621 104640 AAATTTCAAGTTGGAGTAGG 85 719 780670 N/A N/A 105660 105679 GTCATATAGTGGCCCCTAAA 31 720 780671 N/A N/A 106100 106119 CACTGGTATGCCCTTCCAAC 65 721 780672 N/A N/A 106561 106580 GAATTTCTTACTTGTCTTAA 95 722 780673 N/A N/A 107953 107972 GCTACATAAAATAAATCACC 79 723 780674 N/A N/A 109817 109836 AGAGTCTGAAGTATCTAGAA 98 724 780675 N/A N/A 110040 110059 TGAAGCCTGGAACCAGTTTA 94 725 780676 N/A N/A 110227 110246 CCTAAAGCCAATTAGCACAA 101 726 780677 N/A N/A 110637 110656 AGTGTAGCCACTAAGAATTT 88 727 780678 N/A N/A 110978 110997 CTTATACACTAATTGGCTCT 66 728 780679 N/A N/A 111011 111030 TTTCTTCCACCATTCCCTTA 101 729 780680 N/A N/A 111182 111201 CTCACTAATTGCAAAGAAAA 109 730 780681 N/A N/A 111343 111362 CAAAGCTTCAGACTGTGATC 70 731 780682 N/A N/A 111843 111862 TCAGAGAGGCCCGCCATGGG 122 732 780683 N/A N/A 111897 111916 TTCACATGGCTGAAGTCTTG 115 733 780684 N/A N/A 112310 112329 ATCTACTGAATTCTGGTTAG 103 734 780685 N/A N/A 112349 112368 GCACACAGTGTAGTCATACT 44 735 780686 N/A N/A 114870 114889 AACCCAAGATTCCCCCTGGT 99 736 780687 N/A N/A 115427 115446 TGGAGAAGTAAGCTAACAGT 109 737 780688 N/A N/A 115958 115977 TAACTGAAAATTCAAGCCTG 115 738 780689 N/A N/A 116039 116058 CTTAAGGAAAATGAGCTCTC 106 739 780690 N/A N/A 116174 116193 TATAATATCTAGCTTTCCCT 95 740 780691 N/A N/A 116253 116272 CAGAGGGAGAAAAACACTGA 110 741 780692 N/A N/A 116357 116376 CCCTTGAGGGTGTCACAATC 82 742 780693 N/A N/A 116374 116393 ATCTTTGTATCTCTGCTCCC 89 743 780694 N/A N/A 116669 116688 TTGAAATAATAAGTAAAGAT 123 744 780695 N/A N/A 116874 116893 ATAAGACATGCCTCTTTAAG 74 745 780696 N/A N/A 117178 117197 AGTACATATTATTTAACTGC 61 746 780697 N/A N/A 117306 117325 ACTGTTGGTTTTGGCTCACA 66 747 780698 N/A N/A 117646 117665 TCTGGAGACTGACCCACGCA 73 748 780699 N/A N/A 118398 118417 GCTGAGTGGAGGTATCTGCC 92 749 780700 N/A N/A 119907 119926 ATATGGTTTAGGAGAGACTA 41 750 780701 N/A N/A 121039 121058 ATACTTAACTCATGGATAGA 80 751 780702 N/A N/A 121425 121444 AAAAGTGCAATTGCCATAGG 57 752 780703 N/A N/A 121530 121549 CCGGTAACATTTTATTTACC 62 753 780704 N/A N/A 121871 121890 TCAATGTATTGTTGCCAAAT 45 754 780705 N/A N/A 122553 122572 ATGAGCTACCCACACAGTCA 78 755 780706 N/A N/A 123081 123100 TTGGAAGGATGGAGACATCG 28 756 780707 N/A N/A 123885 123904 TGATATGGCATGATGTCTAC 67 757 780708 N/A N/A 124062 124081 AGATGATATGCTATGACATA 77 758 780709 N/A N/A 124679 124698 TGTCCTGTCTCATAACATCT 68 759 780710 N/A N/A 125144 125163 AGAATATTTATGCACTAAAC 71 760 780711 N/A N/A 125277 125296 GTTCTAACAGCAATTTCCTT 78 761 780712 N/A N/A 126145 126164 ATCCTTATGTCCTCACAGAT 89 762 780713 N/A N/A 126446 126465 TATTTCCTCTCAATGTTTAT 125 763 780714 N/A N/A 127216 127235 TTAAAAAAAGGAATGGGATA 92 764 780715 N/A N/A 127242 127261 CAACCTGAAAAAATTAGTCT 79 765 780716 N/A N/A 127360 127379 ATAAATGAGTTGATCAGTGG 83 766 780717 N/A N/A 127443 127462 TATTCCTGGATGAGAAAAAT 103 767 780718 N/A N/A 127460 127479 CCTAAGACTGGTTAAAATAT 91 768 780719 N/A N/A 128188 128207 ATAAGGAAAGTTGTTCTGGG 108 769 780720 N/A N/A 132660 132679 ATGCAATAACAATTATGCAC 75 770 780721 N/A N/A 133278 133297 GGAGTTGATATTTCAGGTAC 81 771 780722 N/A N/A 134443 134462 TTTTCAGAGGATCTACTGTG 90 772 780723 N/A N/A 136265 136284 TAAATGTGAGGAAATATTTG 94 773 780724 N/A N/A 137896 137915 CATATGTATAGTCCGTGAAT 81 774 780725 N/A N/A 138142 138161 TCACTGAGGAATGTGATAAA 108 775 780726 N/A N/A 138369 138388 TTTATTGACAGCTTACCAGG 83 776 780727 N/A N/A 138502 138521 AGCAAAAAACAAAGGAGTCA 94 777 780728 N/A N/A 138562 138581 GAGAACAGTGAGAAGTACAA 100 778 780729 N/A N/A 138891 138910 TAGAGATCTGAGTCAATTTC 70 779 780730 N/A N/A 139058 139077 GCTACTGTGAAGGAAAACAT 66 780 780731 N/A N/A 139370 139389 ATCCAAATGTTAACCACATA 60 781 780732 N/A N/A 139871 139890 ACAGGAGATACTTGTTCAGA 62 782 780733 N/A N/A 140263 140282 TAGAAAATAGTTCCAATTAG 86 783 780734 N/A N/A 140887 140906 CCTTAAAATATTTCCCTTTC 115 784 780735 N/A N/A 141689 141708 AAAGATAATTCTTTTGGGAA 129 785 780736 N/A N/A 144735 144754 GTACAAATATGAGTATTTAG 65 786 144754 144773

Example 4: Effect of 5-10-5 MOE Gapmers with Mixed Internucleoside Linkages on Human LRRK2 RNA Expression In Vitro, Single Dose

Modified oligonucleotides complementary to a human LRRK2 nucleic acid were designed and tested for their effect on LRRK2 RNA in vitro. The modified oligonucleotides were tested in a series of experiments that had similar culture conditions.

Cultured SH-SY5Y cells at a density of 20,000 cells per well were transfected using electroporation with 4,000 nM concentration of modified oligonucleotide or no modified oligonucleotide for untreated controls. After approximately 24 hours, RNA was isolated from the cells and LRRK2 RNA levels were measured by quantitative real-time PCR using human primer probe set RTS3132 as described in Example 2. LRRK2 RNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented in the table below as percent LRRK2 RNA levels relative to untreated control cells. The modified oligonucleotides with percent control values marked with an asterisk (*) target the amplicon region of the primer probe set. Additional assays may be used to measure the potency and efficacy of oligonucleotides targeting the amplicon region.

The modified oligonucleotides in Tables 10-50 are 5-10-5 MOE gapmers. The gapmers are 20 nucleobases in length, wherein the central gap segment comprises ten 2′-deoxynucleosides and is flanked by wing segments on both the 5′ end and on the 3′ end comprising five 2′-MOE nucleosides. The sugar motif for the gapmers is (from 5′ to 3′): eeeeeddddddddddeeeee; wherein ‘d’ represents a 2′-deoxyribose sugar and ‘e’ represents a 2′-MOE modified sugar. All cytosine residues throughout each gapmer are 5-methyl cytosines. The internucleoside linkages for each gapmer are mixed phosphodiester and phosphorothioate linkages. The internucleoside linkage motif for the gapmers is (from 5′ to 3′): sooosssssssssssooss; wherein ‘o’ represents a phosphodiester internucleoside linkage and ‘s’ represents a phosphorothioate internucleoside linkage. “Start Site” indicates the 5′-most nucleoside to which the gapmer is complementary in the human nucleic acid sequence. “Stop Site” indicates the 3′-most nucleoside to which the gapmer is complementary in the human nucleic acid sequence.

Each modified oligonucleotide listed in Tables 10-50 below is complementary to human LRRK2 nucleic acid sequences SEQ ID NO: 1 or SEQ ID NO: 2, as indicated. ‘N/A’ indicates that the modified oligonucleotide is not complementary to that particular nucleic acid sequence with 100% complementarity. As shown below, modified oligonucleotides complementary to the sequence of human LRRK2 RNA reduced the amount of human LRRK2 RNA.

TABLE 10 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′) control NO 693426 185 204 3304 3323 TCCTGGACATTGTTCAGCCT 39 55 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 19 235 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 37 235 802613 10 29 3129 3148 GAGCTCAGCTCACCGCCCGC 99 787 802614 33 52 3152 3171 GCCGGCCACAGCTCCCCGGG 138 788 802615 80 99 3199 3218 CCGCCCTCCCAGCATGAACG 89 789 802616 89 108 3208 3227 TCCAACCCGCCGCCCTCCCA 122 790 802617 109 128 3228 3247 TAGCCATGGTGGCACCTGCT 68 791 802618 118 137 3237 3256 AGCTGCCACTAGCCATGGTG 126 792 802619 127 146 3246 3265 ACCCCTGACAGCTGCCACTA 83 793 802620 136 155 3255 3274 CCTCTTCGCACCCCTGACAG 106 794 802621 198 217 3317 3336 TATCTGTTTTCCTTCCTGGA 67 795 802622 199 218 3318 3337 CTATCTGTTTTCCTTCCTGG 46 796 802623 200 219 3319 3338 TCTATCTGTTTTCCTTCCTG 50 797 802624 201 220 3320 3339 TTCTATCTGTTTTCCTTCCT 42 798 802625 202 221 3321 3340 TTTCTATCTGTTTTCCTTCC 69 799 802626 204 223 3323 3342 CGTTTCTATCTGTTTTCCTT 46 800 802627 222 241 3341 3360 CTCCAGGATTTGGACCAGCG 45 801 802628 231 250 3350 3369 CAGCAGATCCTCCAGGATTT 91 802 802629 240 259 3359 3378 CGTGAACACCAGCAGATCCT 68 803 802630 280 299 3671 3690 TATTTTTGCCTTGAAATAAC 104 804 802631 289 308 3680 3699 GCACATGGATATTTTTGCCT 38 805 802632 298 317 3689 3708 TCAACAGAGGCACATGGATA 60 806 802633 324 343 3715 3734 GACTCTCATATAGGAGTCCA 124 807 802634 333 352 3724 3743 CACACTCGCGACTCTCATAT 109 808 802635 342 361 N/A N/A CACCTGCTGCACACTCGCGA 58 809 802636 351 370 N/A N/A TGACCAACCCACCTGCTGCA 101 810 802637 371 390 10395 10414 TCTATTAATTTGCACAGAAG 104 811 802638 380 399 10404 10423 GGACAGACTTCTATTAATTT 61 812 802639 389 408 10413 10432 ATTGTACCTGGACAGACTTC 53 813 802640 426 445 10450 10469 ATCATTTCCAACATCCTGGG 82 814 802641 435 454 10459 10478 GACTTCCCAATCATTTCCAA 98 815 802642 460 479 N/A N/A TAAGAATCAATTGGTGAACA 62 816 802643 469 488 13735 13754 TTAGCATTTTAAGAATCAAT 49 817 802644 480 499 13746 13765 ATTATGAACTGTTAGCATTT 47 818 802645 504 523 13770 13789 AATCACTGACAAGTTTACAC 74 819 802646 513 532 13779 13798 CTTCAGTCCAATCACTGACA 54 820 802647 522 541 13788 13807 ATCTAAGGTCTTCAGTCCAA 80 821 802648 534 553 13800 13819 AGTTAGGAGGAGATCTAAGG 106 822 802649 535 554 13801 13820 AAGTTAGGAGGAGATCTAAG 96 823 802650 536 555 13802 13821 GAAGTTAGGAGGAGATCTAA 87 824 802651 537 556 13803 13822 TGAAGTTAGGAGGAGATCTA 94 825 802652 538 557 13804 13823 CTGAAGTTAGGAGGAGATCT 58 826 802653 540 559 13806 13825 ACCTGAAGTTAGGAGGAGAT 41 827 802654 541 560 13807 13826 TACCTGAAGTTAGGAGGAGA 53 828 802655 542 561 13808 13827 TTACCTGAAGTTAGGAGGAG 33 829 802656 543 562 N/A N/A TTTACCTGAAGTTAGGAGGA 55 830 802657 544 563 N/A N/A TTTTACCTGAAGTTAGGAGG 56 831 802658 548 567 N/A N/A GTGATTTTACCTGAAGTTAG 53 832 802659 557 576 16077 16096 ATCAGCAAGGTGATTTTACC 61 833 802660 566 585 16086 16105 TCATCCAATATCAGCAAGGT 78 834 802661 575 594 16095 16114 TCACTTTCTTCATCCAATAT 53 835 802662 602 621 16122 16141 ATGGCATCAAAAATTAACAT 47 836 802663 603 622 16123 16142 CATGGCATCAAAAATTAACA 40 837 802664 605 624 16125 16144 TGCATGGCATCAAAAATTAA 75 838 802665 607 626 16127 16146 AGTGCATGGCATCAAAAATT 56 839 802666 609 628 16129 16148 TGAGTGCATGGCATCAAAAA 68 840 802667 610 629 16130 16149 ATGAGTGCATGGCATCAAAA 62 841 802668 612 631 16132 16151 AAATGAGTGCATGGCATCAA 54 842 802669 613 632 16133 16152 GAAATGAGTGCATGGCATCA 49 843 802670 620 639 16140 16159 TTGGCTGGAAATGAGTGCAT 42 844 802671 638 657 16158 16177 AGTTTCTGGACTTCATCATT 95 845 802672 647 666 16167 16186 TTGCATCCAAGTTTCTGGAC 70 846 802673 656 675 16176 16195 TGTAAAGCTTTGCATCCAAG 73 847 802674 682 701 N/A N/A CCTCTGAGACTCTCTCAAAC 41 848 802675 691 710 18590 18609 TCAGTTGCTCCTCTGAGACT 51 849 802676 700 719 18599 18618 CAAATTCAGTCAGTTGCTCC 69 850 802677 726 745 18625 18644 CAATATCATATAATCTTTGT 101 851 802678 735 754 18634 18653 CGCACTTAACAATATCATAT 34 852 802679 744 763 18643 18662 ATTTGTTAACGCACTTAACA 63 853 802680 753 772 18652 18671 ATCTTTAAAATTTGTTAACG 136 854 802681 773 792 18672 18691 TGAAGCACAATTTCCTCTTC 51 855 802682 782 801 18681 18700 TGCAGCACATGAAGCACAAT 67 856 802683 791 810 18690 18709 TGTAAACAATGCAGCACATG 77 857 802684 817 836 N/A N/A CATTATTGCAAGGAATCGCT 58 858 802685 826 845 N/A N/A GGACTTCCACATTATTGCAA 32 859 802686 835 854 21666 21685 CACTCATGAGGACTTCCACA 34 860 802687 861 880 21692 21711 CACAATATTATAACACCTGA 50 861 802688 879 898 21710 21729 TGCTTTCATAGCTTCCACCA 32 862

TABLE 11 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′) control NO 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 42 235 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 17 235 802689 880 899 21711 21730 ATGCTTTCATAGCTTCCACC 24 863 802690 882 901 21713 21732 GAATGCTTTCATAGCTTCCA 36 864 802691 884 903 21715 21734 GGGAATGCTTTCATAGCTTC 30 865 802692 886 905 21717 21736 TAGGGAATGCTTTCATAGCT 36 866 802693 887 906 21718 21737 ATAGGGAATGCTTTCATAGC 44 867 802694 889 908 21720 21739 TCATAGGGAATGCTTTCATA 53 868 802695 890 909 21721 21740 CTCATAGGGAATGCTTTCAT 44 869 802696 891 910 21722 21741 ACTCATAGGGAATGCTTTCA 25 870 802697 892 911 21723 21742 CACTCATAGGGAATGCTTTC 48 871 802698 893 912 21724 21743 TCACTCATAGGGAATGCTTT 29 872 802699 894 913 21725 21744 TTCACTCATAGGGAATGCTT 41 873 802700 895 914 21726 21745 TTTCACTCATAGGGAATGCT 19 874 802701 897 916 21728 21747 TCTTTCACTCATAGGGAATG 27 875 802702 898 917 21729 21748 TTCTTTCACTCATAGGGAAT 40 876 802703 899 918 21730 21749 ATTCTTTCACTCATAGGGAA 35 877 802704 900 919 21731 21750 AATTCTTTCACTCATAGGGA 40 878 802705 901 920 21732 21751 GAATTCTTTCACTCATAGGG 30 879 802706 905 924 21736 21755 TCTTGAATTCTTTCACTCAT 43 880 802707 915 934 21746 21765 GCAACTCACTTCTTGAATTC 53 881 802708 924 943 21755 21774 GAGCAAACAGCAACTCACTT 71 882 802709 949 968 N/A N/A AAAAATTACCTAATGTAAGC 112 883 802710 958 977 27933 27952 GGATATTGAAAAAATTACCT 55 884 802711 967 986 27942 27961 TTAATACCAGGATATTGAAA 88 885 802712 989 1008 27964 27983 ACCACAAACTCATGGACTTC 42 886 802713 990 1009 27965 27984 CACCACAAACTCATGGACTT 34 887 802714 991 1010 27966 27985 TCACCACAAACTCATGGACT 45 888 802715 992 1011 27967 27986 TTCACCACAAACTCATGGAC 61 889 802716 993 1012 27968 27987 TTTCACCACAAACTCATGGA 45 890 802717 998 1017 27973 27992 ACAGCTTTCACCACAAACTC 35 891 802718 1007 1026 27982 28001 TACTGCTGCACAGCTTTCAC 40 892 802719 1016 1035 27991 28010 TTCTCTGGGTACTGCTGCAC 47 893 802720 1055 1074 28030 28049 AGGGCCAAACAGCTGAGCGC 70 894 802721 1064 1083 N/A N/A TCAGTGAGGAGGGCCAAACA 83 895 802722 1090 1109 29351 29370 CTAAATCTTGATTTAAGAAA 134 896 802723 1099 1118 29360 29379 TCTTTTCCTCTAAATCTTGA 55 897 802724 1111 1130 29372 29391 CTTGATTCTCATTCTTTTCC 47 898 802725 1132 1151 29393 29412 CTTCCCCCTCATCATCATTC 58 899 802726 1141 1160 29402 29421 ATTTATCTTCTTCCCCCTCA 43 900 802727 1150 1169 29411 29430 GCCAAAACAATTTATCTTCT 44 901 802728 1176 1195 29437 29456 CGTTAATGCTTTGTAACAGG 26 902 802729 1194 1213 29455 29474 CTTGTTCTTTCTATGCCACG 64 903 802730 1225 1244 29576 29595 TTAGTGCCCAGCATGCGGCC 37 904 802731 1234 1253 29585 29604 GGAGATTATTTAGTGCCCAG 20 905 802732 1243 1262 29594 29613 GGTACATAAGGAGATTATTT 30 906 802733 1269 1288 29620 29639 TCCAATCTTCTCATGTAAAC 99 907 802734 1278 1297 29629 29648 ATCTTCATCTCCAATCTTCT 93 908 802735 1287 1306 N/A N/A GAAATGGCCATCTTCATCTC 110 909 802736 1313 1332 31029 31048 GAGAGCATCACTTCCCTATG 47 910 802737 1322 1341 31038 31057 ATCAGCATGGAGAGCATCAC 48 911 802738 1331 1350 31047 31066 GAAGAATGCATCAGCATGGA 58 912 802739 1357 1376 31073 31092 CAGATGCCTGGAAAACTTCC 51 913 802740 1366 1385 31082 31101 ATGCATTCGCAGATGCCTGG 43 914 802741 1375 1394 31091 31110 GAGTTGACAATGCATTCGCA 59 915 802742 1385 1404 31101 31120 TGTTCTAAGAGAGTTGACAA 85 916 802743 1426 1445 35373 35392 GTATTCCTTTTGATAACAGT 24 917 802744 1435 1454 35382 35401 CATTCAGGTGTATTCCTTTT 27 918 802745 1444 1463 35391 35410 ACTCCAAAACATTCAGGTGT 40 919 802746 1470 1489 35417 35436 AGGAGAATGTATATGCTTCT 18 920 802747 1479 1498 35426 35445 AGCCACTTCAGGAGAATGTA 27 921 802748 1488 1507 35435 35454 GCCACTTTCAGCCACTTCAG 21 922 802749 1514 1533 35461 35480 TCAAAAAGATGATTTAGCAT 113 923 802750 1523 1542 N/A N/A TTGCTTCCTTCAAAAAGATG 78 924 802751 1533 1552 N/A N/A CAGGGAAGTGTTGCTTCCTT 53 925 802752 1574 1593 37623 37642 ATAACTGTTAGTATTTTGGG 34 926 802753 1607 1626 37656 37675 AGCTGCACTGGTAATGATGT 57 927 802754 1631 1650 37680 37699 TGTAAAATAGCTCGAAGCGC 90 928 802755 1654 1673 N/A N/A CTGGCATGCCAGGCACTATA 62 929 802756 1663 1682 N/A N/A TGGATTCTTCTGGCATGCCA 40 930 802757 1672 1691 41905 41924 TATCCTCCCTGGATTCTTCT 69 931 802758 1699 1718 41932 41951 CCATATTTAGCTTATGATGA 20 932 802759 1708 1727 41941 41960 GTTTTTTAACCATATTTAGC 38 933 802760 1717 1736 41950 41969 TGAAACACTGTTTTTTAACC 48 934 802761 1743 1762 41976 41995 TAGGACCAGTTTGTGAATAT 72 935 802762 1752 1771 41985 42004 CAAAGCTGCTAGGACCAGTT 69 936 802763 1761 1780 N/A N/A GAACCTGTTCAAAGCTGCTA 47 937 802764 1770 1789 N/A N/A ATTTCCAATGAACCTGTTCA 71 938 802765 1784 1803 52698 52717 TTCTGAATCCCAGGATTTCC 38 939

TABLE 12 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′) control NO 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 42 235 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 50 235 802766 1785 1804 52699 52718 TTTCTGAATCCCAGGATTTC 140 940 802767 1787 1806 52701 52720 CATTTCTGAATCCCAGGATT 97 941 802768 1788 1807 52702 52721 ACATTTCTGAATCCCAGGAT 60 942 802769 1790 1809 52704 52723 CCACATTTCTGAATCCCAGG 41 943 802770 1792 1811 52706 52725 ATCCACATTTCTGAATCCCA 57 944 802771 1794 1813 52708 52727 TAATCCACATTTCTGAATCC 119 945 802772 1806 1825 52720 52739 AGAAATTACTTTTAATCCAC 97 946 802773 1815 1834 52729 52748 TACAATAGAAGAAATTACTT 176 947 802774 1835 1854 52749 52768 TCTAATGCATCAGGAAAATG 145 948 802775 1844 1863 52758 52777 GATAACATCTCTAATGCATC 56 949 802776 1853 1872 52767 52786 CCTTCCAGGGATAACATCTC 125 950 802777 1862 1881 52776 52795 TCCATAGCACCTTCCAGGGA 73 951 802778 1868 1887 52782 52801 ACTGAATCCATAGCACCTTC 52 952 802779 1869 1888 52783 52802 CACTGAATCCATAGCACCTT 63 953 802780 1870 1889 52784 52803 GCACTGAATCCATAGCACCT 44 954 802781 1871 1890 52785 52804 AGCACTGAATCCATAGCACC 65 955 802782 1872 1891 52786 52805 AAGCACTGAATCCATAGCAC 70 956 802783 1874 1893 52788 52807 TGAAGCACTGAATCCATAGC 100 957 802784 1875 1894 52789 52808 GTGAAGCACTGAATCCATAG 53 958 802785 1876 1895 52790 52809 TGTGAAGCACTGAATCCATA 107 959 802786 1877 1896 52791 52810 GTGTGAAGCACTGAATCCAT 62 960 802787 1878 1897 52792 52811 TGTGTGAAGCACTGAATCCA 73 961 802788 1882 1901 52796 52815 GCAGTGTGTGAAGCACTGAA 100 962 802789 1891 1910 52805 52824 GATACATCTGCAGTGTGTGA 116 963 802790 1900 1919 52814 52833 GGTCATCTGGATACATCTGC 77 964 802791 1909 1928 N/A N/A GAATTTCTTGGTCATCTGGA 106 965 802792 1928 1947 52968 52987 AGACTTAAACCCAGACACTG 78 966 802793 1937 1956 52977 52996 TATCCTATAAGACTTAAACC 157 967 802794 1946 1965 52986 53005 GTAATCAAGTATCCTATAAG 105 968 802795 1972 1991 53012 53031 CAGTTCCTATGAACACATTC 76 969 802796 1981 2000 53021 53040 GCAGATGTCCAGTTCCTATG 79 970 802797 1990 2009 53030 53049 TTTTTGCCAGCAGATGTCCA 117 971 802798 1999 2018 53039 53058 AAACCAGAATTTTTGCCAGC 81 972 802799 2018 2037 53058 53077 TTAAATCGGTATAAGCTGGA 112 973 802800 2027 2046 53067 53086 GCAACATCCTTAAATCGGTA 78 974 802801 2036 2055 53076 53095 TGTATTTCAGCAACATCCTT 145 975 802802 2062 2081 N/A N/A CTAAGATTGTCTGAAATCCT 84 976 802803 2071 2090 56005 56024 TGAGGATTGCTAAGATTGTC 84 977 802804 2080 2099 56014 56033 CTGACAATTTGAGGATTGCT 58 978 802805 2106 2125 56040 56059 ATGCACCAGCAGCTTAGAAA 71 979 802806 2115 2134 56049 56068 AAATGAATGATGCACCAGCA 82 980 802807 2124 2143 56058 56077 TACTAAGTCAAATGAATGAT 109 981 802808 2151 2170 56085 56104 GATATTGGAAGACATTTGAT 143 982 802809 2160 2179 56094 56113 TTGTTCCATGATATTGGAAG 128 983 802810 2180 2199 N/A N/A TTTAGAAACTGTTGATCCTT 113 984 802811 2181 2200 N/A N/A GTTTAGAAACTGTTGATCCT 128 985 802812 2182 2201 N/A N/A GGTTTAGAAACTGTTGATCC 93 986 802813 2183 2202 N/A N/A AGGTTTAGAAACTGTTGATC 115 987 802814 2184 2203 N/A N/A GAGGTTTAGAAACTGTTGAT 118 988 802815 2186 2205 N/A N/A CAGAGGTTTAGAAACTGTTG 63 989 802816 2187 2206 N/A N/A ACAGAGGTTTAGAAACTGTT 84 990 802817 2188 2207 N/A N/A AACAGAGGTTTAGAAACTGT 119 991 802818 2189 2208 N/A N/A CAACAGAGGTTTAGAAACTG 99 992 802819 2190 2209 56198 56217 GCAACAGAGGTTTAGAAACT 94 993 802820 2194 2213 56202 56221 ACTTGCAACAGAGGTTTAGA 109 994 802821 2203 2222 56211 56230 TTGCAAAACACTTGCAACAG 120 995 802822 2212 2231 56220 56239 TAGCTACTTTTGCAAAACAC 88 996 802823 2238 2257 56246 56265 CATCACATTTTTTAAGTAAT 100 997 802824 2247 2266 56255 56274 TCTCTCTAGCATCACATTTT 80 998 802825 2256 2275 56264 56283 ATCACACGCTCTCTCTAGCA 57 999 802826 2282 2301 56290 56309 CATTCAACCATGATGCTGTT 79 72 802827 2291 2310 56299 56318 AGAAGCAAGCATTCAACCAT 103 1000 802828 2300 2319 56308 56327 GCTCCCAATAGAAGCAAGCA 108 1001 802829 2312 2331 56320 56339 TGATTGGCATCTGCTCCCAA 96 1002 802830 2313 2332 56321 56340 TTGATTGGCATCTGCTCCCA 67 1003 802831 2314 2333 56322 56341 CTTGATTGGCATCTGCTCCC 87 1004 802832 2315 2334 56323 56342 GCTTGATTGGCATCTGCTCC 54 1005 802833 2316 2335 56324 56343 TGCTTGATTGGCATCTGCTC 83 1006 802834 2318 2337 56326 56345 TTTGCTTGATTGGCATCTGC 82 125 802835 2319 2338 56327 56346 CTTTGCTTGATTGGCATCTG 80 1007 802836 2320 2339 56328 56347 CCTTTGCTTGATTGGCATCT 70 1008 802837 2321 2340 56329 56348 TCCTTTGCTTGATTGGCATC 94 1009 802838 2322 2341 56330 56349 CTCCTTTGCTTGATTGGCAT 75 1010 802839 2326 2345 56334 56353 ATCCCTCCTTTGCTTGATTG 124 1011 802840 2335 2354 56343 56362 TTAAAGAAGATCCCTCCTTT 186 1012 802841 2344 2363 56352 56371 CCTGACAAATTAAAGAAGAT 148 1013 802842 2357 2376 N/A N/A TCTTTCTCACATACCTGACA 69 1014

TABLE 13 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′) control NO 693433 2380 2399 62001 62020 GTTCCACCAATTTGGGACTG 41 126 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 30 235 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 22 235 802843 2358 2377 N/A N/A CTCTTTCTCACATACCTGAC 74 1015 802844 2360 2379 N/A N/A CTCTCTTTCTCACATACCTG 53 1016 802845 2365 2384 61986 62005 GACTGCTCTCTTTCTCACAT 34 1017 802846 2367 2386 61988 62007 GGGACTGCTCTCTTTCTCAC 39 1018 802847 2369 2388 61990 62009 TTGGGACTGCTCTCTTTCTC 53 1019 802848 2370 2389 61991 62010 TTTGGGACTGCTCTCTTTCT 59 1020 802849 2372 2391 61993 62012 AATTTGGGACTGCTCTCTTT 99 1021 802850 2373 2392 61994 62013 CAATTTGGGACTGCTCTCTT 83 1022 802851 2389 2408 62010 62029 TCAGTAAGAGTTCCACCAAT 65 1023 802852 2415 2434 62036 62055 TACATCTTGTTCACGAGATC 92 1024 802853 2460 2479 62081 62100 GATCTGGCTGTCACCTTTCC 65 1025 802854 2469 2488 62090 62109 CAAGCTGATGATCTGGCTGT 98 1026 802855 2478 2497 62099 62118 CCTTAAGAGCAAGCTGATGA 58 1027 802856 2487 2506 62108 62127 GGCCAGCCTCCTTAAGAGCA 74 1028 802857 2508 2527 62129 62148 GCTATTGTTGGCCACATCCA 44 1029 802858 2517 2536 62138 62157 AAGGCAAATGCTATTGTTGG 90 1030 802859 2526 2545 62147 62166 AAATCCTCCAAGGCAAATGC 92 1031 802860 2552 2571 62173 62192 CAAGAAGGTTCAACTTTTCC 87 1032 802861 2596 2615 62217 62236 GTTTCCTTAAATTAGAAGTC 169 1033 802862 2606 2625 N/A N/A ATATTTGTTTGTTTCCTTAA 81 1034 802863 2615 2634 N/A N/A GTAGATGCTATATTTGTTTG 82 1035 802864 2641 2660 65479 65498 GATATCTGATCACCATTCTT 78 1036 802865 2650 2669 65488 65507 TTTTCATCTGATATCTGATC 121 1037 802866 2659 2678 65497 65516 CCACAGCACTTTTCATCTGA 116 1038 802867 2668 2687 65506 65525 TTCCTTCTTCCACAGCACTT 115 1039 802868 2687 2706 65525 65544 CCATCGCTGCCTGAGGCTGT 69 1040 802869 2696 2715 65534 65553 GAAAAATTTCCATCGCTGCC 149 1041 802870 2705 2724 65543 65562 ACATCTTCAGAAAAATTTCC 86 1042 802871 2731 2750 65569 65588 AGGTCCATTCATCAAATTTA 77 1043 802872 2740 2759 65578 65597 CAGGAATAAAGGTCCATTCA 68 1044 802873 2749 2768 65587 65606 TAGAAGAGTCAGGAATAAAG 119 1045 802874 2761 2780 65599 65618 ACACACTGTCCATAGAAGAG 53 1046 802875 2763 2782 65601 65620 AAACACACTGTCCATAGAAG 102 1047 802876 2765 2784 65603 65622 GCAAACACACTGTCCATAGA 43 1048 802877 2767 2786 65605 65624 GAGCAAACACACTGTCCATA 42 1049 802878 2768 2787 65606 65625 TGAGCAAACACACTGTCCAT 70 1050 802879 2770 2789 65608 65627 TTTGAGCAAACACACTGTCC 124 1051 802880 2771 2790 65609 65628 CTTTGAGCAAACACACTGTC 141 1052 802881 2778 2797 65616 65635 GTCATCACTTTGAGCAAACA 90 1053 802882 2787 2806 65625 65644 ACTATCCAGGTCATCACTTT 121 1054 802883 2796 2815 N/A N/A ACTTCCTTCACTATCCAGGT 53 1055 802884 2819 2838 71662 71681 TTTTTCACAAGAAATGAGCC 96 1056 802885 2828 2847 71671 71690 TTAGATTTCTTTTTCACAAG 116 1057 802886 2837 2856 71680 71699 CTAATTGAATTAGATTTCTT 106 1058 802887 2863 2882 71706 71725 CGGCATCTCGGTAAAATTCT 48 1059 802888 2872 2891 71715 71734 GCTGTAATACGGCATCTCGG 27 1060 802889 2907 2926 71750 71769 GGAATTGGAATGTCTTTGCA 76 1061 802890 2916 2935 N/A N/A GGGCCCCAAGGAATTGGAAT 102 1062 802891 2925 2944 N/A N/A ATCAAAAATGGGCCCCAAGG 87 1063 802892 2951 2970 72975 72994 CTTTTTCGCTTCAGTAAATC 79 1064 802893 2962 2981 72986 73005 ATAATATTTTTCTTTTTCGC 109 1065 802894 2971 2990 72995 73014 CATCTGAAGATAATATTTTT 141 1066 802895 2995 3014 N/A N/A GAAGTTTTGATGACCTGAGT 108 1067 802896 3004 3023 73540 73559 TATGGGATTGAAGTTTTGAT 56 1068 802897 3013 3032 73549 73568 AATGCCTCATATGGGATTGA 93 1069 802898 3022 3041 73558 73577 TGCTGTCTGAATGCCTCATA 60 1070 802899 3040 3059 73576 73595 CAGAAGCCAGAGAAGAAATG 135 1071 802900 3049 3068 73585 73604 ATTCTCTCTCAGAAGCCAGA 53 1072 802901 3058 3077 73594 73613 ATGTAATATATTCTCTCTCA 52 1073 802902 3084 3103 73620 73639 TAGTTCATTTGCTGAAAGGT 66 1074 802903 3093 3112 73629 73648 AATATCTCTTAGTTCATTTG 146 1075 802904 3102 3121 73638 73657 TAGGGCATCAATATCTCTTA 40 1076 802905 3111 3130 73647 73666 TTTCTGGCTTAGGGCATCAA 133 1077 802906 3129 3148 73665 73684 ATGAACACTTATACAGCATT 114 1078 802907 3138 3157 73674 73693 ATGCTCCAAATGAACACTTA 124 1079 802908 3147 3166 73683 73702 CTTTTCAAGATGCTCCAAAT 170 1080 802909 3173 3192 73709 73728 GTGAGTGCATTCTGGTGAAG 72 1081 802910 3192 3211 73728 73747 TAGCTGTTGTGGAAAGCTCG 114 1082 802911 3217 3236 N/A N/A GTGTCAAACTCTTCAGAGTT 34 1083 802912 3218 3237 76352 76371 TGTGTCAAACTCTTCAGAGT 60 1084 802913 3219 3238 76353 76372 ATGTGTCAAACTCTTCAGAG 63 1085 802914 3220 3239 76354 76373 AATGTGTCAAACTCTTCAGA 99 1086 802915 3226 3245 76360 76379 AGTCCAAATGTGTCAAACTC 23 1087 802916 3235 3254 76369 76388 TACTGTGCAAGTCCAAATGT 119 1088 802917 3244 3263 76378 76397 TAAATTTATTACTGTGCAAG 55 1089 802918 3265 3284 76399 76418 ACAAATAAGAAGGAAATGAT 196 1090

TABLE 14 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′) control NO 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 22 235 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 29 235 802919 3274 3293 76408 76427 TCATTTTCAACAAATAAGAA 110 1091 802920 3283 3302 76417 76436 CAATACAACTCATTTTCAAC 63 1092 802921 3309 3328 76443 76462 GTCATTTCGAGAGACATCAA 36 1093 802922 3318 3337 76452 76471 GGGTCCAATGTCATTTCGAG 38 1094 802923 3327 3346 76461 76480 AACCACTGAGGGTCCAATGT 51 1095 802924 3353 3372 76487 76506 GTTGGACATTTCACTGTAGG 20 1096 802925 3362 3381 76496 76515 TGTTTCAGAGTTGGACATTT 77 1097 802926 3371 3390 76505 76524 AGGTTAAACTGTTTCAGAGT 36 1098 802927 3380 3399 76514 76533 TTATATGACAGGTTAAACTG 103 1099 802928 3398 3417 76532 76551 GGTACAAAAGACAGCTGGTT 34 1100 802929 3407 3426 76541 76560 AGGTTCTCAGGTACAAAAGA 47 1101 802930 3416 3435 76550 76569 ACATCAGTGAGGTTCTCAGG 37 1102 802931 3442 3461 76576 76595 AAATGAGCTGCTCCAGTTTC 75 1103 802932 3451 3470 N/A N/A TTCCTTCTAAAATGAGCTGC 53 1104 802933 3463 3482 N/A N/A CTGATATTTTATTTCCTTCT 69 1105 802934 3472 3491 77221 77240 AGCATATCCCTGATATTTTA 29 1106 802935 3495 3514 77244 77263 CAGTTCCTTCAGTCTCAAGG 32 1107 802936 3496 3515 77245 77264 TCAGTTCCTTCAGTCTCAAG 49 1108 802937 3497 3516 77246 77265 TTCAGTTCCTTCAGTCTCAA 80 1109 802938 3498 3517 77247 77266 CTTCAGTTCCTTCAGTCTCA 37 1110 802939 3499 3518 77248 77267 TCTTCAGTTCCTTCAGTCTC 56 1111 802940 3505 3524 77254 77273 TTAAAATCTTCAGTTCCTTC 59 1112 802941 3514 3533 77263 77282 TACTAAGGTTTAAAATCTTC 105 1113 802942 3523 3542 77272 77291 TGTGGTTCTTACTAAGGTTT 38 1114 802943 3547 3566 77296 77315 GAAAGTTCTCTGATAGGGAT 59 1115 802944 3556 3575 77305 77324 AAGCCTCAAGAAAGTTCTCT 59 1116 802945 3565 3584 77314 77333 CTTTAGGACAAGCCTCAAGA 65 132 802946 3591 3610 77340 77359 ATTCATTCTGGCACTGAAAC 136 1117 802947 3600 3619 N/A N/A AGCAAGAAAATTCATTCTGG 75 1118 802948 3609 3628 N/A N/A AGGCATAGCAGCAAGAAAAT 57 1119 802949 3635 3654 80915 80934 AGGATTGTCATAGAAGGAGG 19 1120 802950 3644 3663 80924 80943 GATAATTTTAGGATTGTCAT 58 1121 802951 3654 3673 80934 80953 TTTGTTCTGAGATAATTTTA 32 1122 802952 3679 3698 80959 80978 AAATTGCTTCTGGAATACAG 75 1123 802953 3688 3707 80968 80987 GAAGATTTAAAATTGCTTCT 115 1124 802954 3697 3716 N/A N/A GCAAGTGTGGAAGATTTAAA 50 1125 802955 3709 3728 N/A N/A TATCTAAAGACCGCAAGTGT 51 1126 802956 3710 3729 N/A N/A ATATCTAAAGACCGCAAGTG 62 1127 802957 3711 3730 N/A N/A CATATCTAAAGACCGCAAGT 63 1128 802958 3712 3731 82057 82076 TCATATCTAAAGACCGCAAG 71 1129 802959 3713 3732 82058 82077 CTCATATCTAAAGACCGCAA 47 1130 802960 3715 3734 82060 82079 TGCTCATATCTAAAGACCGC 35 1131 802961 3716 3735 82061 82080 CTGCTCATATCTAAAGACCG 43 1132 802962 3717 3736 82062 82081 GCTGCTCATATCTAAAGACC 28 1133 802963 3718 3737 82063 82082 TGCTGCTCATATCTAAAGAC 64 1134 802964 3719 3738 82064 82083 TTGCTGCTCATATCTAAAGA 79 1135 802965 3723 3742 82068 82087 ATCATTGCTGCTCATATCTA 82 1136 802966 3732 3751 82077 82096 GTACTGAATATCATTGCTGC 31 1137 802967 3741 3760 82086 82105 ACCTGGTAGGTACTGAATAT 50 1138 802968 3767 3786 82112 82131 AAGTTCAAAGATTTCCAGTG 50 1139 802969 3776 3795 82121 82140 AGTTCCCTTAAGTTCAAAGA 78 1140 802970 3785 3804 82130 82149 CTAAATAAGAGTTCCCTTAA 75 1141 802971 3811 3830 82156 82175 AGTCCAAGATGCTGATCTGA 49 1142 802972 3820 3839 82165 82184 TTTCACTCAAGTCCAAGATG 52 1143 802973 3829 3848 82174 82193 AATATGCTTTTTCACTCAAG 64 1144 802974 3855 3874 82200 82219 ATGCAGTTTCTCTACTCTAG 31 1145 802975 3864 3883 82209 82228 GTGAGAAAGATGCAGTTTCT 47 1146 802976 3873 3892 82218 82237 CAGTTTATTGTGAGAAAGAT 89 1147 802977 3882 3901 N/A N/A AATCTCTTTCAGTTTATTGT 65 1148 802978 3900 3919 83895 83914 ACAGCCAATCTCAGGAGGAA 56 1149 802979 3909 3928 83904 83923 ATTTTCAAGACAGCCAATCT 72 1150 802980 3918 3937 83913 83932 AGATGTCAGATTTTCAAGAC 141 1151 802981 3944 3963 83939 83958 AGTTCCAAGTTGTAACTGAC 59 57 802982 3953 3972 83948 83967 AAGGATCTTAGTTCCAAGTT 89 1152 802983 3962 3981 83957 83976 TCATTGGGAAAGGATCTTAG 107 1153 802984 3988 4007 83983 84002 CCCATATTTTGCTTAATTTC 54 1154 802985 3997 4016 83992 84011 AAGGAAGATCCCATATTTTG 72 1155 802986 4006 4025 84001 84020 GTTCATCCAAAGGAAGATCC 40 1156 802987 4033 4052 84028 84047 TATGTTTAAAATCAAAGTTA 128 1157 802988 4042 4061 84037 84056 TACATCCTATATGTTTAAAA 101 1158 802989 4060 4079 84055 84074 TTATGATGTCTTTGGCTTTA 41 1159 802990 4061 4080 84056 84075 CTTATGATGTCTTTGGCTTT 53 1160 802991 4063 4082 84058 84077 ACCTTATGATGTCTTTGGCT 36 1161 802992 4065 4084 N/A N/A AAACCTTATGATGTCTTTGG 41 1162 802993 4068 4087 N/A N/A AAGAAACCTTATGATGTCTT 80 1163 802994 4078 4097 N/A N/A ATCGCTGTTGAAGAAACCTT 38 1164 802995 4087 4106 86582 86601 CCTTTTTTAATCGCTGTTGA 69 1165

TABLE 15 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′) control NO 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 31 235 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 51 235 802996 4096 4115 86591 86610 AAGGCACAGCCTTTTTTAAT 88 1166 802997 4106 4125 86601 86620 ATTCGGTTATAAGGCACAGC 39 1167 802998 4107 4126 86602 86621 CATTCGGTTATAAGGCACAG 54 1168 802999 4108 4127 86603 86622 TCATTCGGTTATAAGGCACA 51 1169 803000 4109 4128 86604 86623 TTCATTCGGTTATAAGGCAC 34 1170 803001 4110 4129 86605 86624 TTTCATTCGGTTATAAGGCA 47 1171 803002 4112 4131 86607 86626 AGTTTCATTCGGTTATAAGG 57 1172 803003 4113 4132 86608 86627 AAGTTTCATTCGGTTATAAG 72 1173 803004 4114 4133 86609 86628 TAAGTTTCATTCGGTTATAA 89 1174 803005 4115 4134 86610 86629 ATAAGTTTCATTCGGTTATA 44 1175 803006 4116 4135 86611 86630 CATAAGTTTCATTCGGTTAT 45 1176 803007 4120 4139 86615 86634 CAATCATAAGTTTCATTCGG 51 1177 803008 4129 4148 86624 86643 TATTTCCCACAATCATAAGT 98 1178 803009 4138 4157 86633 86652 CACTCCCAGTATTTCCCACA 69 1179 803010 4164 4183 86659 86678 TAATTGCTGCAATAAGGTGG 51 1180 803011 4173 4192 86668 86687 GGTTTTCATTAATTGCTGCA 40 1181 803012 4184 4203 86679 86698 TCTGATTTCTTGGTTTTCAT 58 1182 803013 4208 4227 86703 86722 ACTGTGGCACTTTGCATTCC 80 1183 803014 4217 4236 86712 86731 TCTATGCCAACTGTGGCACT 79 1184 803015 4226 4245 86721 86740 TCTTTCACATCTATGCCAAC 79 1185 803016 4252 4271 86747 86766 TTTTGTCTCTTATTTGGATA 44 1186 803017 4267 4286 86762 86781 CGAGATCTCTCTTTCTTTTG 56 1187 803018 4276 4295 86771 86790 CATTTAGGACGAGATCTCTC 92 1188 803019 4296 4315 N/A N/A ACGACCTGCAAAATCCCACA 65 1189 803020 4305 4324 N/A N/A GAATTCCTCACGACCTGCAA 90 83 803021 4314 4333 87218 87237 AGTACTATAGAATTCCTCAC 35 1190 803022 4359 4378 87263 87282 ATAGACAGCAAGGTACAATG 101 1191 803023 4368 4387 87272 87291 GCTGAGGTCATAGACAGCAA 101 1192 803024 4377 4396 87281 87300 CTGTCCCTTGCTGAGGTCAT 89 1193 803025 4403 4422 87307 87326 CAAGGCTTCATGGCATCAAC 85 1194 803026 4412 4431 87316 87335 TTGAAGAGCCAAGGCTTCAT 96 1195 803027 4421 4440 N/A N/A GCCTTTATATTGAAGAGCCA 62 1196 803028 4456 4475 88557 88576 TGCCAACGAGAATCACAGGG 45 1197 803029 4465 4484 88566 88585 CCAAATGTGTGCCAACGAGA 70 1198 803030 4474 4493 88575 88594 CAGAAACATCCAAATGTGTG 69 1199 803031 4505 4524 88606 88625 TTACTCATGCAGGCTTTGCG 44 1200 803032 4514 4533 88615 88634 TTGGTGATTTTACTCATGCA 43 1201 803033 4536 4555 88637 88656 CCCTCGCTTATTCAGGAGTT 98 1202 803034 4545 4564 88646 88665 GGCAGGGAACCCTCGCTTAT 61 1203 803035 4580 4599 88681 88700 TCCTCGGTGGCATTCACAAA 60 42 803036 4589 4608 88690 88709 GCATCAGATTCCTCGGTGGC 39 1204 803037 4598 4617 88699 88718 TTTGCCAAAGCATCAGATTC 67 1205 803038 4639 4658 N/A N/A TCTTGAAATTAAGGCTCTCG 91 1206 803039 4648 4667 N/A N/A GATCTCGGATCTTGAAATTA 125 1207 803040 4668 4687 92091 92110 CAGCTGTCCAACAACAAGCT 81 1208 803041 4677 4696 92100 92119 GTCTGGAATCAGCTGTCCAA 55 1209 803042 4686 4705 92109 92128 TACATAGCAGTCTGGAATCA 75 1210 803043 4712 4731 92135 92154 TCCGATAAAATGATTTTTTC 60 1211 803044 4721 4740 92144 92163 TTTTTACGCTCCGATAAAAT 132 1212 803045 4730 4749 92153 92172 ATTGGCACATTTTTACGCTC 24 1213 803046 4756 4775 92179 92198 GTTTCCGGTCAATTACGGGA 21 1214 803047 4775 4794 92198 92217 CTCACTAGTTGTAATAATCG 63 1215 803048 4800 4819 92223 92242 TTCATCTAACTGCAGCTGAT 59 1216 803049 4810 4829 92233 92252 GAAGCTCATTTTCATCTAAC 49 1217 803050 4844 4863 N/A N/A ACTCCTGATTCATTTAGAAA 88 1218 803051 4853 4872 N/A N/A TGAAGAAGGACTCCTGATTC 99 1219 803052 4862 4881 93323 93342 TCTTGAAAATGAAGAAGGAC 100 1220 803053 4871 4890 93332 93351 AGTGCTGGGTCTTGAAAATG 55 1221 803054 4892 4911 93353 93372 AAGTACAAGTCACTTAACTG 38 1222 803055 4938 4957 N/A N/A TGTCAAAATCTGTGCCATGA 70 1223 803056 4947 4966 98095 98114 CACTTTCACTGTCAAAATCT 76 1224 803057 4956 4975 98104 98123 ACAACCTTCCACTTTCACTG 65 1225 803058 4982 5001 98130 98149 GAAATAATGCCCTTAGGGTG 98 1226 803059 4991 5010 98139 98158 TCTCTACGCGAAATAATGCC 58 1227 803060 5000 5019 98148 98167 TTTTCCACATCTCTACGCGA 49 1228 803061 5009 5028 98157 98176 GAAAGAAATTTTTCCACATC 65 1229 803062 5028 5047 98176 98195 TGGAAATTTCCTTTTTTTTG 81 1230 803063 5038 5057 98186 98205 TGTAGTTCTTTGGAAATTTC 45 1231 803064 5047 5066 98195 98214 ACTGTGACATGTAGTTCTTT 29 1232 803065 5072 5091 98220 98239 TGGAATTTTTCTAGGAGCTT 23 1233 803066 5082 5101 98230 98249 CAAAGCAATCTGGAATTTTT 104 1234 803067 5091 5110 98239 98258 TCCTATTGGCAAAGCAATCT 79 1235 803068 5100 5119 98248 98267 ATATTCTTCTCCTATTGGCA 84 1236 803069 5118 5137 N/A N/A ACTGCTTGGAACCAGCAAAT 72 1237 803070 5127 5146 N/A N/A GTCAGACAAACTGCTTGGAA 84 1238 803071 5136 5155 99142 99161 AGGCCTGTGGTCAGACAAAC 87 1239 803072 5145 5164 99151 99170 CTCTATCACAGGCCTGTGGT 73 1240

TABLE 16 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′) control NO 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 11 235 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 26 235 803073 5178 5197 99184 99203 GATGATAATTTCAGAGTTCT 49 1241 803074 5187 5206 99193 99212 ATATAGTCGGATGATAATTT 53 1242 803075 5196 5215 99202 99221 AGGCATTTCATATAGTCGGA 11 1243 803076 5206 5225 99212 99231 TTGGAAAATAAGGCATTTCA 48 1244 803077 5227 5246 99233 99252 TTAATCTTGACCAAAATCCC 76 1245 803078 5236 5255 99242 99261 ATCGATTGATTAATCTTGAC 48 1246 803079 5245 5264 99251 99270 TCTCAAGTAATCGATTGATT 34 1247 803080 5270 5289 99276 99295 CTCCCTGAAAGCATGTAAGG 64 1248 803081 5294 5313 100146 100165 CTGTTTGGGCGAAGTGCTCG 45 1249 803082 5300 5319 100152 100171 TACATTCTGTTTGGGCGAAG 52 1250 803083 5301 5320 100153 100172 ATACATTCTGTTTGGGCGAA 40 1251 803084 5302 5321 100154 100173 AATACATTCTGTTTGGGCGA 33 1252 803085 5303 5322 100155 100174 CAATACATTCTGTTTGGGCG 39 1253 803086 5304 5323 100156 100175 CCAATACATTCTGTTTGGGC 48 1254 803087 5306 5325 100158 100177 CGCCAATACATTCTGTTTGG 36 1255 803088 5307 5326 100159 100178 TCGCCAATACATTCTGTTTG 44 1256 803089 5308 5327 100160 100179 GTCGCCAATACATTCTGTTT 57 1257 803090 5309 5328 100161 100180 TGTCGCCAATACATTCTGTT 55 1258 803091 5310 5329 100162 100181 TTGTCGCCAATACATTCTGT 62 1259 803092 5314 5333 100166 100185 TGCCTTGTCGCCAATACATT 46 1260 803093 5323 5342 100175 100194 TTAAGTAAATGCCTTGTCGC 61 1261 803094 5332 5351 100184 100203 GAGACCAATTTAAGTAAATG 63 1262 803095 5358 5377 100210 100229 AGATCCTACCAGACAATAAG 83 1263 803096 5367 5386 100219 100238 TAAGACTTCAGATCCTACCA 49 1264 803097 5376 5395 100228 100247 ATGATTGTCTAAGACTTCAG 38 1265 803098 5385 5404 100237 100256 ACTCTCTGGATGATTGTCTA 36 1266 803099 5405 5424 100257 100276 GGAACTGTAATTTTTAAGAA 98 1267 803100 5414 5433 100266 100285 CTACAAGAAGGAACTGTAAT 98 1268 803101 5423 5442 N/A N/A CAGCCTTTTCTACAAGAAGG 40 1269 803102 5449 5468 100438 100457 GGTCCACAACTTGGCCCAAA 28 1270 803103 5458 5477 100447 100466 AATCAATGTGGTCCACAACT 70 1271 803104 5467 5486 100456 100475 CCATGAGAGAATCAATGTGG 35 1272 803105 5476 5495 100465 100484 ACCATTCTTCCATGAGAGAA 36 1273 803106 5497 5516 100486 100505 CAATCTCCAGCAACCCAGGA 69 1274 803107 5507 5526 100496 100515 CCACAAATATCAATCTCCAG 45 1275 803108 5516 5535 100505 100524 TCTCCTTCACCACAAATATC 46 1276 803109 5533 5552 100522 100541 ATTTCTTCAACAGAGTTTCT 103 1277 803110 5534 5553 100523 100542 CATTTCTTCAACAGAGTTTC 64 1278 803111 5536 5555 100525 100544 CCCATTTCTTCAACAGAGTT 36 1279 803112 5538 5557 100527 100546 TGCCCATTTCTTCAACAGAG 22 1280 803113 5540 5559 100529 100548 AATGCCCATTTCTTCAACAG 53 1281 803114 5541 5560 100530 100549 TAATGCCCATTTCTTCAACA 67 1282 803115 5551 5570 100540 100559 TAAAACTATATAATGCCCAT 49 1283 803116 5560 5579 100549 100568 CACCATCATTAAAACTATAT 72 1284 803117 5586 5605 100575 100594 ATCAAGTAAGATTTTTTGAT 84 1285 803118 5595 5614 100584 100603 CATCAAGTCATCAAGTAAGA 70 1286 803119 5604 5623 100593 100612 TGCTTTCTTCATCAAGTCAT 80 1287 803120 5631 5650 101269 101288 TGGATTTACTAAGAGATCTC 36 1288 803121 5640 5659 101278 101297 TGGTTGATCTGGATTTACTA 49 1289 803122 5649 5668 101287 101306 GGTGAGCCTTGGTTGATCTG 28 1290 803123 5689 5708 101327 101346 CAGCCAAAATCAAGTCAGGG 29 1291 803124 5698 5717 101336 101355 TAGGCAGGTCAGCCAAAATC 47 1292 803125 5721 5740 101359 101378 ATCATTATTCAACATAATAT 78 1293 803126 5730 5749 101368 101387 TTCCAACTCATCATTATTCA 37 1294 803127 5739 5758 101377 101396 TTGTTCAAATTCCAACTCAT 79 1295 803128 5763 5782 N/A N/A ATCACCTAGGAGAAACTCTG 52 1296 803129 5772 5791 N/A N/A AAAACTGCCATCACCTAGGA 60 1297 803130 5781 5800 106472 106491 AACTGATCCAAAACTGCCAT 51 1298 803131 5807 5826 106498 106517 TCTTCTCCTTCATAGGCTGC 55 1299 803132 5816 5835 106507 106526 ACAGCCACTTCTTCTCCTTC 80 1300 803133 5825 5844 106516 106535 AAAATCTTCACAGCCACTTC 102 92 803134 5851 5870 106542 106561 ACAGCCTGAGTGATGTATGT 32* 1301 803135 5860 5879 106551 106570 CTTGTCTTAACAGCCTGAGT 28* 1302 803136 5869 5888 N/A N/A CCACAAGCTCTTGTCTTAAC 34* 1303 803137 5909 5928 113106 113125 AGCAAAGATATCAAACTGGG 51* 1304 803138 5918 5937 113115 113134 CCAGCTGCCAGCAAAGATAT 44* 1305 803139 5927 5946 113124 113143 GGACGAATCCCAGCTGCCAG 42* 1306 803140 5955 5974 113152 113171 GGAGGCTAACTCCATCACCA 35 1307 803141 5964 5983 113161 113180 GGAACCCTTGGAGGCTAACT 89 1308 803142 5973 5992 113170 113189 GCGATCCAAGGAACCCTTGG 91 1309 803143 5999 6018 113196 113215 AGGCTGGCTTTGTCCTGCTG 110 1310 803144 6008 6027 113205 113224 GTTCTAGTGAGGCTGGCTTT 75 1311 803145 6017 6036 113214 113233 TGCTGTAGGGTTCTAGTGAG 93 1312 803146 6052 6071 N/A N/A ATCTCAAACCATCAGCTACG 76 1313 803147 6061 6080 N/A N/A AGTGGAGGTATCTCAAACCA 85 1314 803148 6087 6106 118420 118439 CAGGTCTCGGTATATAATCA 69 1315 803149 6111 6130 118444 118463 GAAAAGCAGCACATTGTGGG 47 1316

TABLE 17 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′) control NO 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 12 235 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 24 235 803150 6131 6150 118464 118483 GCAGCATTGGGATACAGTGT 53 1317 803151 6140 6159 118473 118492 GCAATGATGGCAGCATTGGG 59 1318 803152 6149 6168 118482 118501 GCAATCTTTGCAATGATGGC 56 159 803153 6189 6208 118522 118541 TATCCCCATTCTACAGCAGT 81 1319 803154 6198 6217 118531 118550 TGATGTTTTTATCCCCATTC 98 1320 803155 6220 6239 N/A N/A CACGAAACCCTGGTGTGCCC 58 1321 803156 6229 6248 124860 124879 CTTCAGGTGCACGAAACCCT 101 1322 803157 6238 6257 124869 124888 CTCTGGCAACTTCAGGTGCA 65 1323 803158 6264 6283 124895 124914 AGCCTGTTGGTTATAAATGA 64 1324 803159 6273 6292 124904 124923 ATAAACATCAGCCTGTTGGT 83 1325 803160 6282 6301 124913 124932 ACCAAATGAATAAACATCAG 60 1326 803161 6308 6327 124939 124958 GTTGTCAAAATGTCATAGAG 57 1327 803162 6317 6336 124948 124967 CTACCTCCAGTTGTCAAAAT 72 1328 803163 6326 6345 124957 124976 TCTACTATTCTACCTCCAGT 57 1329 803164 6335 6354 124966 124985 TTCAAACCCTCTACTATTCT 85 1330 803165 6354 6373 124985 125004 ATCAAACTCATTTGGAAACT 71 1331 803166 6363 6382 124994 125013 TTCTAATTCATCAAACTCAT 90 1332 803167 6372 6391 125003 125022 TCCTTGTATTTCTAATTCAT 93 1333 803168 6398 6417 N/A N/A TATTCTTTAACTGGATCAGG 81 1334 803169 6407 6426 126523 126542 GCACAACCATATTCTTTAAC 70 1335 803170 6442 6461 126558 126577 ACTGTTTAATTAATTTCTCA 60 1336 803171 6451 6470 126567 126586 CTTTCAAACACTGTTTAATT 68 1337 803172 6460 6479 126576 126595 GAGGATTTTCTTTCAAACAC 39 1338 803173 6486 6505 N/A N/A GACCTGGGCAGAAGTAGGCC 62 1339 803174 6495 6514 N/A N/A AATGTCAAAGACCTGGGCAG 94 1340 803175 6504 6523 129649 129668 TGAATTCAAAATGTCAAAGA 113 1341 803176 6548 6567 129693 129712 TTTTTAGGTAATAAAATGCG 112 1342 803177 6577 6596 129722 129741 GTGTAGCAACCATGCATTCA 32 1343 803178 6586 6605 129731 129750 TGTTGTGATGTGTAGCAACC 54 162 803179 6595 6614 129740 129759 CATTCCTGCTGTTGTGATGT 66 1344 803180 6607 6626 129752 129771 GCCAAATGCTTGCATTCCTG 42 1345 803181 6608 6627 129753 129772 AGCCAAATGCTTGCATTCCT 38 1346 803182 6609 6628 129754 129773 CAGCCAAATGCTTGCATTCC 64 1347 803183 6610 6629 129755 129774 CCAGCCAAATGCTTGCATTC 53 1348 803184 6611 6630 129756 129775 CCCAGCCAAATGCTTGCATT 59 1349 803185 6613 6632 129758 129777 AGCCCAGCCAAATGCTTGCA 43 163 803186 6614 6633 129759 129778 CAGCCCAGCCAAATGCTTGC 73 1350 803187 6615 6634 129760 129779 ACAGCCCAGCCAAATGCTTG 97 1351 803188 6616 6635 129761 129780 CACAGCCCAGCCAAATGCTT 90 1352 803189 6617 6636 129762 129781 CCACAGCCCAGCCAAATGCT 104 1353 803190 6621 6640 129766 129785 GTGCCCACAGCCCAGCCAAA 60 1354 803191 6630 6649 129775 129794 TCTGTCGGTGTGCCCACAGC 77 1355 803192 6639 6658 129784 129803 GAGCTGTCCTCTGTCGGTGT 71 1356 803193 6665 6684 129810 129829 CCTTCAGTATTTAAGTCAAG 75 1357 803194 6674 6693 129819 129838 GAAGTGTATCCTTCAGTATT 76 1358 803195 6683 6702 N/A N/A ACTTCCTCAGAAGTGTATCC 89 1359 803196 6709 6728 132419 132438 CTAAGCACAATATTCTACTA 65 1360 803197 6718 6737 132428 132447 GCACCAAGGCTAAGCACAAT 54 1361 803198 6727 6746 132437 132456 CAGGAAGATGCACCAAGGCT 53 1362 803199 6753 6772 132463 132482 AGACACAATCCAGCTTTCCT 113 1363 803200 6762 6781 132472 132491 CTGTGTCCCAGACACAATCC 91 1364 803201 6771 6790 132481 132500 AGTACCAGACTGTGTCCCAG 74 1365 803202 6797 6816 132507 132526 CCATCTTCGGTATTGATGAC 57 1366 803203 6806 6825 132516 132535 CTCTTTTTCCCATCTTCGGT 61 1367 803204 6815 6834 132525 132544 AGGGTATGTCTCTTTTTCCC 42 1368 803205 6841 6860 132551 132570 AAGTGACAGAATCAGTCATC 71 52 803206 6850 6869 132560 132579 AATACAAACAAGTGACAGAA 98 1369 803207 6864 6883 132574 132593 GGAAAAGGAATTGCAATACA 76 1370 803208 6902 6921 134234 134253 GTTCCAACCAAAAGAAAATT 86 1371 803209 6911 6930 134243 134262 CCATCAGCGGTTCCAACCAA 55 1372 803210 6929 6948 134261 134280 TCAAAAATTGCTAACTTGCC ill 1373 803211 6938 6957 134270 134289 GTCTTATCTTCAAAAATTGC 92 1374 803212 6947 6966 N/A N/A AGCTTAACAGTCTTATCTTC 94 1375 803213 6973 6992 137377 137396 GTATCTTCAAAGGAGCAGCT 72 1376 803214 6983 7002 137387 137406 CCTATATTTAGTATCTTCAA 54 1377 803215 6992 7011 137396 137415 CTGACATTTCCTATATTTAG 73 1378 803216 7017 7036 137421 137440 TTCACTCAAACACATCAATG 68 1379 803217 7026 7045 137430 137449 ATTTGTGGATTCACTCAAAC 72 1380 803218 7035 7054 137439 137458 TTCCGTTGAATTTGTGGATT 85 1381 803219 7061 7080 137465 137484 CCACATCCTCCCCACATTAC 62 1382 803220 7070 7089 137474 137493 ATCTTTGTGCCACATCCTCC 77 1383 803221 7087 7106 137491 137510 CATTAGAAAAGGAGAAAATC 85 1384 803222 7105 7124 137509 137528 GTTTCTGAATGGTGAAATCA 76 1385 803223 7114 7133 137518 137537 TCTCAATGAGTTTCTGAATG 74 1386 803224 7123 7142 137527 137546 TTGTTCTTGTCTCAATGAGT 100 1387 803225 7132 7151 137536 137555 ACAGTTGGCTTGTTCTTGTC 104 1388 803226 7150 7169 141511 141530 TGAAAGCTGCATAAGAAAAC 116 1389

TABLE 18 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′) control NO 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 25 235 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 20 235 803227 7159 7178 141520 141539 TGGAATCACTGAAAGCTGCA 65 1390 803228 7168 7187 141529 141548 TTATGATGTTGGAATCACTG 60 1391 803229 7194 7213 141555 141574 ATAGAGAGCAGTGTCTACCA 66 1392 803230 7203 7222 141564 141583 CTTAGCAATATAGAGAGCAG 97 1393 803231 7212 7231 141573 141592 GCTATTTTGCTTAGCAATAT 46 1394 803232 7238 7257 141599 141618 TTCTTATCCCACACTTCCAC 89 1395 803233 7248 7267 141609 141628 TTTTTCAGTTTTCTTATCCC 75 1396 803234 7257 7276 141618 141637 TCCACAGAGTTTTTCAGTTT 64 1397 803235 7282 7301 141643 141662 TTAAAAAGTGCACGCAGTCT 108 1398 803236 7291 7310 N/A N/A TTACCTCCCTTAAAAAGTGC 95 1399 803237 7300 7319 N/A N/A CTTTTACCATTACCTCCCTT 80 1400 803238 7309 7328 142957 142976 CCTTGTTTTCTTTTACCATT 65 1401 803239 7339 7358 142987 143006 TCCCAGAATAAGACATTTTG 68 1402 803240 7348 7367 142996 143015 TTTTCACTCTCCCAGAATAA 62 1403 803241 7371 7390 143019 143038 AGTGTTCTTCTGAAGGCAGA 60 1404 803242 7380 7399 143028 143047 CCAAAGAGCAGTGTTCTTCT 86 1405 803243 7389 7408 143037 143056 AGTTCCTATCCAAAGAGCAG 87 1406 803244 7415 7434 143063 143082 TCCAGGAGTAAAATATGGCC 51 1407 803245 7424 7443 143072 143091 GTTGAAAGATCCAGGAGTAA 106 1408 803246 7433 7452 143081 143100 AGTCGACGAGTTGAAAGATC 106 1409 803247 7466 7485 143114 143133 ACCGAATTACAAAAGTTGTA 71 1410 803248 7475 7494 143123 143142 ATGACTCTGACCGAATTACA 82 1411 803249 7484 7503 143132 143151 GCTGTCATCATGACTCTGAC 65 1412 803250 7510 7529 145113 145132 TGACATTTTTAAGGCTTCCT 58 1413 803251 7522 7541 145125 145144 CCAATACCAGCATGACATTT 75 1414 803252 7531 7550 145134 145153 GGTTGTAGCCCAATACCAGC 74 1415 803253 7554 7573 145157 145176 TTGTGTACCTTCAGTATTTT 61 1416 803254 7564 7583 145167 145186 CTTTCTGCTTTTGTGTACCT 92 1417 803255 7573 7592 N/A N/A ATTGTATCTCTTTCTGCTTT 104 1418 803256 7598 7617 145767 145786 TTGATGTCCCAAACGGTCAA 49 1419 803257 7607 7626 145776 145795 TGTGGAAGATTGATGTCCCA 96 1420 803258 7616 7635 145785 145804 TGCACTTCATGTGGAAGATT 74 1421 803259 7625 7644 145794 145813 TCTAAATTTTGCACTTCATG 71 1422 803260 7645 7664 145814 145833 TTCTCACTTCAATGTGTTTT 48 1423 803261 7654 7673 145823 145842 CTAATTCTTTTCTCACTTCA 93 1424 803262 7666 7685 145835 145854 TCATTTTTTCAGCTAATTCT 95 1425 803263 7697 7716 145866 145885 CTATTTCTCTCTTACTCAAC 77 1426 803264 7706 7725 145875 145894 AGACAATTCCTATTTCTCTC 45 1427 803265 7717 7736 145886 145905 TTCCTATCCAAAGACAATTC 83 1428 803266 7741 7760 145910 145929 TATTTACAAGAGGAGAGAAT 75 1429 803267 7771 7790 145940 145959 CCCTTTCCATGTGAACATTT 65 1430 803268 7772 7791 145941 145960 ACCCTTTCCATGTGAACATT 49 1431 803269 7773 7792 145942 145961 TACCCTTTCCATGTGAACAT 49 1432 803270 7774 7793 145943 145962 GTACCCTTTCCATGTGAACA 41 1433 803271 7775 7794 145944 145963 AGTACCCTTTCCATGTGAAC 54 1434 803272 7777 7796 145946 145965 TGAGTACCCTTTCCATGTGA 43 1435 803273 7778 7797 145947 145966 GTGAGTACCCTTTCCATGTG 44 1436 803274 7779 7798 145948 145967 TGTGAGTACCCTTTCCATGT 66 1437 803275 7780 7799 145949 145968 ATGTGAGTACCCTTTCCATG 37 1438 803276 7781 7800 145950 145969 AATGTGAGTACCCTTTCCAT 57 1439 803277 7785 7804 145954 145973 AAAAAATGTGAGTACCCTTT 68 1440 803278 7794 7813 145963 145982 AGCTATTTCAAAAAATGTGA 89 1441 803279 7803 7822 145972 145991 ATACACACGAGCTATTTCAA 76 1442 803280 7812 7831 145981 146000 CATTCCTTCATACACACGAG 57 1443 803281 7850 7869 146019 146038 GTAAGTATTTTTACATATAT 69 1444 803282 7876 7895 146045 146064 TAGTTCTTTAAAATACACAT 58 1445 803283 7888 7907 146057 146076 TTGTGTTTTAAATAGTTCTT 56 1446 803284 7897 7916 146066 146085 AATATAACATTGTGTTTTAA 95 1447 803285 7921 7940 146090 146109 CGAAAGTAACTGGTATTTAT 40 1448 803286 7930 7949 146099 146118 ATTAATGAACGAAAGTAACT 125 1449 803287 7939 7958 146108 146127 TTTTCATTAATTAATGAACG 99 1450 803288 7948 7967 146117 146136 ACAGATTTATTTTCATTAAT 82 1451 803289 7969 7988 146138 146157 AGTACTTAAATTAGGTACTT 126 1452 803290 7978 7997 146147 146166 TTTAGTATGAGTACTTAAAT 102 1453 803291 7987 8006 146156 146175 CTTATAAATTTTAGTATGAG 98 1454 803292 8019 8038 146188 146207 CATTACAGACAAGAAAACAA 109 1455 803293 8028 8047 146197 146216 GTTTACCTCCATTACAGACA 61 1456 803294 8037 8056 146206 146225 TAAAATAAAGTTTACCTCCA 59 1457 803295 8061 8080 146230 146249 TAGTCCTGTCTTAAGCACAG 74 1458 803296 8070 8089 146239 146258 GACAAGCAATAGTCCTGTCT 66 1459 803297 8079 8098 146248 146267 AGAAAAATCGACAAGCAATA 89 1460 803298 8105 8124 146274 146293 ATTTTCATTATACCGTGCAG 55 1461 803299 8116 8135 146285 146304 ACTGTCTTAATATTTTCATT 53 1462 803300 8125 8144 146294 146313 ACATGGGAAACTGTCTTAAT 56 1463 803301 8149 8168 146318 146337 ATGCAATCTAAGAAGGAATA 67 1464 803302 8158 8177 146327 146346 TGCATTTCGATGCAATCTAA 36 1465 803303 8167 8186 146336 146355 ATATGATAGTGCATTTCGAT 69 1466

TABLE 19 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′) control NO 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 27 235 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 12 235 803304 8176 8195 146345 146364 TACAAGCATATATGATAGTG 83 1467 803305 8207 8226 146376 146395 GACTTTATTAGTGCAAATTC 54 1468 803306 8208 8227 146377 146396 GGACTTTATTAGTGCAAATT 45 1469 803307 8209 8228 146378 146397 AGGACTTTATTAGTGCAAAT 54 1470 803308 8210 8229 146379 146398 AAGGACTTTATTAGTGCAAA 56 1471 803309 8212 8231 146381 146400 CAAAGGACTTTATTAGTGCA 59 1472 803310 8213 8232 146382 146401 ACAAAGGACTTTATTAGTGC 58 1473 803311 8214 8233 146383 146402 AACAAAGGACTTTATTAGTG 63 1474 803312 8215 8234 146384 146403 CAACAAAGGACTTTATTAGT 101 1475 803313 8240 8259 146409 146428 ACAGCAACAAAGAGAATTCA 88 1476 803314 8252 8271 146421 146440 GCACTGTTTGCAACAGCAAC 91 1477 803315 8261 8280 146430 146449 GTGTAAGATGCACTGTTTGC 74 1478 803316 8284 8303 146453 146472 TTTCTTTTGAATTGAGTGAA 92 1479 803317 8293 8312 146462 146481 TAATGGAGTTTTCTTTTGAA 87 1480 803318 8302 8321 146471 146490 TAGTACTTTTAATGGAGTTT 115 1481 803319 8328 8347 146497 146516 TTTGACAGTATGTCATGTTT 118 1482 803320 8337 8356 146506 146525 TATGAGGACTTTGACAGTAT 101 1483 803321 8346 8365 146515 146534 TTTCCTAGATATGAGGACTT 121 1484 803322 8355 8374 146524 146543 TTCTGTGTCTTTCCTAGATA 125 1485 803323 8373 8392 146542 146561 TTCTGTGACAAAGAGAGTTT 73 1486 803324 8382 8401 146551 146570 ACAGAGAGTTTCTGTGACAA 85 1487 803325 8391 8410 146560 146579 AGGAAAGACACAGAGAGTTT 100 1488 803326 8418 8437 146587 146606 GAGTTGAAAAACAACTCTAT 129 1489 803327 8427 8446 146596 146615 TCAAACATAGAGTTGAAAAA 116 1490 803328 8436 8455 146605 146624 TATCCACATTCAAACATAGA 116 1491 803329 8461 8480 146630 146649 TACACTAATTATACAAAATT 114 1492 803330 8470 8489 146639 146658 CACTGTATTTACACTAATTA 73 1493 803331 8479 8498 146648 146667 AGGACTGAACACTGTATTTA 56 1494 803332 8488 8507 146657 146676 ATCACTTGAAGGACTGAACA 73 1495 803333 8524 8543 146693 146712 ACAAGTAGCTAGTGGTATGA 85 1496 803334 8533 8552 146702 146721 GATTAGAAAACAAGTAGCTA 69 1497 803335 8545 8564 146714 146733 TAGAATGAAGCAGATTAGAA 116 1498 803336 8570 8589 146739 146758 TTAGGGAAAAGATGAATATA 93 1499 803337 8579 8598 146748 146767 ATCACAAATTTAGGGAAAAG 72 1500 803338 8588 8607 146757 146776 ATCTGCAGCATCACAAATTT 77 1501 803339 8614 8633 146783 146802 AAAGGTTTCTATCTGAATGA 107 1502 803340 8639 8658 146808 146827 GGAATTCTATAATTCTGAAA 80 1503 803341 8659 8678 146828 146847 ATGGTCTTGGTAGGAGCTGT 77 1504 803342 8668 8687 146837 146856 TTTATCCTCATGGTCTTGGT 56 1505 803343 8677 8696 146846 146865 TGTTAGATATTTATCCTCAT 66 1506 803344 8705 8724 146874 146893 GCTCCTTTCTCCTTCAGCAA 58 1507 803345 8714 8733 146883 146902 ATAACTAAAGCTCCTTTCTC ill 1508 803346 8723 8742 146892 146911 TTATCCATCATAACTAAAGC 112 1509 803347 8732 8751 146901 146920 CAGATATTTTTATCCATCAT 57 1510 803348 8750 8769 146919 146938 TTTGGAAGCCTAGGGTGGCA 80 1511 803349 8759 8778 146928 146947 TAAGTATAATTTGGAAGCCT 69 1512 803350 8768 8787 146937 146956 TAAACAATTTAAGTATAATT 121 1513 803351 8794 8813 146963 146982 TGATACTCCTATTGTGGTAA 89 1514 803352 8803 8822 146972 146991 ATTTGGCCCTGATACTCCTA 71 1515 803353 8812 8831 146981 147000 TACATAGGTATTTGGCCCTG ill 1516 803354 8838 8857 147007 147026 CTAAAGCAGAAATGACCTCA 61 1517 803355 8847 8866 147016 147035 GTACTTTTCCTAAAGCAGAA 74 1518 803356 8856 8875 147025 147044 TTACCGAAAGTACTTTTCCT 89 1519 803357 8882 8901 147051 147070 ATGAATACTGGTCAGGGCCA 102 61 803358 8891 8910 147060 147079 TCTGAAATAATGAATACTGG 85 1520 803359 8900 8919 147069 147088 AGGGAATTATCTGAAATAAT 46 1521 803360 8926 8945 147095 147114 ATTAAATGTACTAGTTGTCC 90 1522 803361 8935 8954 147104 147123 TCTGAGAATATTAAATGTAC 66 1523 803362 8944 8963 147113 147132 GCCATAAGTTCTGAGAATAT 53 1524 803363 8953 8972 147122 147141 TAGTAAAATGCCATAAGTTC 79 1525 803364 8957 8976 147126 147145 CACATAGTAAAATGCCATAA 51 1526 803365 8958 8977 147127 147146 TCACATAGTAAAATGCCATA 63 1527 803366 8959 8978 147128 147147 TTCACATAGTAAAATGCCAT 43 1528 803367 8960 8979 147129 147148 TTTCACATAGTAAAATGCCA 55 1529 803368 8961 8980 147130 147149 TTTTCACATAGTAAAATGCC 80 1530 803369 8963 8982 147132 147151 AGTTTTCACATAGTAAAATG 101 1531 803370 8964 8983 147133 147152 AAGTTTTCACATAGTAAAAT 133 1532 803371 8965 8984 147134 147153 AAAGTTTTCACATAGTAAAA 77 1533 803372 8966 8985 147135 147154 TAAAGTTTTCACATAGTAAA 88 1534 803373 8967 8986 147136 147155 TTAAAGTTTTCACATAGTAA 97 1535 803374 8972 8991 147141 147160 TAAATTTAAAGTTTTCACAT 104 1536 803375 8988 9007 147157 147176 TTACCCTTAATATAAATAAA 113 1537 803376 8997 9016 147166 147185 AGAATTTGATTACCCTTAAT 82 1538 803377 9015 9034 147184 147203 GAAAATCTTTCATCTTTAAG 116 1539 803378 9028 9047 147197 147216 CCTTTAAAATACAGAAAATC 110 1540 803379 9037 9056 147206 147225 GCATAGCTTCCTTTAAAATA 70 1541 803380 9059 9078 147228 147247 GTTAATTACATAACAAGTTA 76 1542

TABLE 20 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′) control NO 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 25 235 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 20 235 803381 9078 9097 147247 147266 TATTATATATGATTTTTTTG 96 1543 803382 9103 9122 147272 147291 GAGATAACACTGGAACAAAG 79 1544 803383 9112 9131 147281 147300 ACAATGAAAGAGATAACACT 96 1545 803384 9125 9144 147294 147313 CAAATACAAAGTAACAATGA 119 1546 803385 9164 9183 147333 147352 GTATTCATTTTTTTAATTTG 95 1547 803386 N/A N/A 3733 3752 TACCTGCTGCACACTCGCGA 32 1548 803387 N/A N/A 4361 4380 ATCCAAGATACATAGCAAAT 61 1549 803388 N/A N/A 4768 4787 TAATAGTCAGATGGAAAATA 92 1550 803389 N/A N/A 5023 5042 TATCAAGCAGGAGTGACTCT 81 1551 803390 N/A N/A 5210 5229 CTCTCTAGGCAGAAATACTA 87 1552 803391 N/A N/A 5227 5246 ATACTTTGCCTCTGGTACTC 80 1553 803392 N/A N/A 5291 5310 CAACTATGATATATCCAAAA 139 1554 803393 N/A N/A 7598 7617 AAAAGATAGGCAGGAAAAGA 185 1555 803394 N/A N/A 8034 8053 TGCCAAACTCATCTCTGTAC 76 1556 803395 N/A N/A 8402 8421 GTAAACAACGGCTATTTTAG 65 1557 803396 N/A N/A 10211 10230 CCCAGAAACAAAAGCAAGCC 70 1558 803397 N/A N/A 11602 11621 GTACTGAAAACAAGAAGAGC 96 1559 803398 N/A N/A 11762 11781 GGACATTTAAAGTTACAATT 66 1560 803399 N/A N/A 12023 12042 TCTTCTTCACAACTGCATGG 71 1561 803400 N/A N/A 12348 12367 TTTACATTATTGGAAGAAGA 84 1562 803401 N/A N/A 12349 12368 CTTTACATTATTGGAAGAAG 96 1563 803402 N/A N/A 12350 12369 GCTTTACATTATTGGAAGAA 64 1564 803403 N/A N/A 12351 12370 GGCTTTACATTATTGGAAGA 46 1565 803404 N/A N/A 12352 12371 TGGCTTTACATTATTGGAAG 52 1566 803405 N/A N/A 12354 12373 TTTGGCTTTACATTATTGGA 69 1567 803406 N/A N/A 12355 12374 GTTTGGCTTTACATTATTGG 40 1568 803407 N/A N/A 12356 12375 TGTTTGGCTTTACATTATTG 68 1569 803408 N/A N/A 12357 12376 TTGTTTGGCTTTACATTATT 85 1570 803409 N/A N/A 12358 12377 ATTGTTTGGCTTTACATTAT 57 1571 803410 N/A N/A 13200 13219 GAATAATTCACAATGTACAC 64 1572 803411 N/A N/A 13280 13299 CATGTGTGTTTGTTTCTTTC 70 1573 803412 N/A N/A 14768 14787 ATTCAAACCTTCCCAATCAC 131 1574 803413 N/A N/A 14988 15007 TCCATCGCCAAATGGAGAAT 102 1575 803414 N/A N/A 15083 15102 AATACTGGAATAGGAGTAGT 98 1576 803415 N/A N/A 15343 15362 TCTCATGATCCTTAGTATGA 72 1577 803416 N/A N/A 15717 15736 ACCTGGCCTACTCCTGTTCC 95 1578 803417 N/A N/A 16619 16638 ATGCATATTAGTCTTTTTCC 61 1579 803418 N/A N/A 18995 19014 CTGCCACTGTAATCACCTCT 54 1580 803419 N/A N/A 19777 19796 TACATATTGTCTAATAATCC 114 1581 803420 N/A N/A 20043 20062 TTTGTTGGCAGTGATGTCTC 49 1582 803421 N/A N/A 20233 20252 TTAAAAACTTTTGATTTCTT 131 1583 803422 N/A N/A 20684 20703 AAGGGCAACCAATGTACAAG 43 1584 803423 N/A N/A 20708 20727 TATGACCTGTTTCCTCCATT 60 1585 803424 N/A N/A 20709 20728 CTATGACCTGTTTCCTCCAT 82 1586 803425 N/A N/A 20710 20729 GCTATGACCTGTTTCCTCCA 37 1587 803426 N/A N/A 20711 20730 AGCTATGACCTGTTTCCTCC 43 1588 803427 N/A N/A 20712 20731 CAGCTATGACCTGTTTCCTC 35 1589 803428 N/A N/A 20714 20733 ATCAGCTATGACCTGTTTCC 69 1590 803429 N/A N/A 20715 20734 AATCAGCTATGACCTGTTTC 70 1591 803430 N/A N/A 20717 20736 AAAATCAGCTATGACCTGTT 72 1592 803431 N/A N/A 20718 20737 TAAAATCAGCTATGACCTGT 88 1593 803432 N/A N/A 21079 21098 ATGTGGTGAATATTATAGAA 38 1594 803433 N/A N/A 21236 21255 CTTTATTGAAAATTGCCACA 43 1595 803434 N/A N/A 22179 22198 CATTTAAGTTGGATAGTGAG 80 1596 803435 N/A N/A 23283 23302 GGAATAAAATATACAATATA 86 1597 803436 N/A N/A 23734 23753 AGTTCTTCTTAAAATGATCC 34 1598 803437 N/A N/A 24259 24278 AAGCCCACATTGAAAAAACA 80 1599 803438 N/A N/A 24494 24513 TGAAAATAAACAGAGAAGAT 93 1600 803439 N/A N/A 24497 24516 ATGTGAAAATAAACAGAGAA 97 1601 803440 N/A N/A 24663 24682 AGCCTAGAAGCAGTTGGTTT 88 1602 803441 N/A N/A 25966 25985 AATAATAACAATATCCCATC 83 1603 803442 N/A N/A 26005 26024 AAGATTGATGAACCACAGGA 51 1604 803443 N/A N/A 26046 26065 ATTTCATCCCTTACTGCTTA 123 1605 803444 N/A N/A 26583 26602 AGAGATAATCAAGAGAAAAA 104 1606 803445 N/A N/A 27062 27081 AGTATGGAGCTCCTTTACCA 66 1607 803446 N/A N/A 28223 28242 TACATTGAGATGTGTATATT ill 1608 803447 N/A N/A 29215 29234 TGCTTTAGGAGAAGCCTTGG 62 1609 803448 N/A N/A 29216 29235 GTGCTTTAGGAGAAGCCTTG 41 1610 803449 N/A N/A 29217 29236 TGTGCTTTAGGAGAAGCCTT 36 1611 803450 N/A N/A 29218 29237 GTGTGCTTTAGGAGAAGCCT 34 1612 803451 N/A N/A 29219 29238 GGTGTGCTTTAGGAGAAGCC 40 1613 803452 N/A N/A 29221 29240 GAGGTGTGCTTTAGGAGAAG 58 1614 803453 N/A N/A 29222 29241 TGAGGTGTGCTTTAGGAGAA 56 1615 803454 N/A N/A 29223 29242 ATGAGGTGTGCTTTAGGAGA 80 1616 803455 N/A N/A 29224 29243 AATGAGGTGTGCTTTAGGAG 68 1617 803456 N/A N/A 29225 29244 GAATGAGGTGTGCTTTAGGA 63 1618 803457 N/A N/A 29927 29946 ATTTTAAAACGATCAGCCAG 87 1619

TABLE 21 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ ID SEQ ID SEQ ID SEQ ID LRRK2 Compound NO: 1 NO: 1 NO: 2 NO: 2 % SEQ Number Start Site Stop Site Start Site Stop Site Sequence (5′ to 3′) control ID NO 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC  16  235 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC  28  235 803458 N/A N/A 30062 30081 AGTTGGGAACTCATCATAGG  79 1620 803459 N/A N/A 30238 30257 AGGCTCACGGATATGAAACA  59 1621 803460 N/A N/A 30698 30717 AAGAGAGGAAAAACTGAAAA  83 1622 803461 N/A N/A 31335 31354 GTTTACACATAGAAGTCCGG  46 1623 803462 N/A N/A 32129 32148 TAAAGGGATACAAGCCATTT  74 1624 803463 N/A N/A 32534 32553 TCCTTGAGAGCAGCCCCTGT  76 1625 803464 N/A N/A 32577 32596 ATTCGAGAACAGCGATTCCC 100 1626 803465 N/A N/A 32857 32876 ACTGAACAAAGACATCAGGG  36 1627 803466 N/A N/A 32987 33006 ATGAACGAGCTACTCAAGTT  79 1628 803467 N/A N/A 32997 33016 AAGAAAGTTGATGAACGAGC  48 1629 803468 N/A N/A 33091 33110 CCTGCCAATGTAGCCATTTT  40 1630 803469 N/A N/A 33163 33182 GAATAGGAAAAATGTCACAC  39 1631 803470 N/A N/A 33422 33441 GTCTTACTCAATAGTCACCT  25 1632 803471 N/A N/A 33499 33518 TCTTGATCTCATCCACTCCA  44 1633 803472 N/A N/A 35580 35599 CAAGTGTCTTATGTTTTTCT  42 1634 803473 N/A N/A 35803 35822 GATTTTATCTTTTATAACTT  75 1635 803474 N/A N/A 36736 36755 TCTGTTTACTTATCAGTCTC  77 1636 803475 N/A N/A 37002 37021 GCAGTAGGTACTATGAACTT  36 1637 803476 N/A N/A 38011 38030 CTTGAACTCAGGTCATGGCA  69 1638 803477 N/A N/A 38572 38591 CTCACCCCCGACCATGTGCA  71 1639 803478 N/A N/A 38768 38787 CACAATGCTATTGTCTTTAG  72 1640 803479 N/A N/A 39901 39920 CATAATGTACATCTTTGCCA  59 1641 803480 N/A N/A 40030 40049 AATGTCTATATAACAAGTTA  80 1642 803481 N/A N/A 40156 40175 TATATCCCTTCTTAAAGAAT  94 1643 803482 N/A N/A 40684 40703 CGTGTGGACTGTAAATTTTT  91 1644 803483 N/A N/A 40840 40859 CATCATGCTACATGTAATGG  59 1645 803484 N/A N/A 41078 41097 TGCTGGGAATACTATGGTAA  64 1646 803485 N/A N/A 41108 41127 ATTCCAATTACATGCCAAGG  49 1647 803486 N/A N/A 41173 41192 ATCTGCATTAATGCAAACTG  71 1648 803487 N/A N/A 41893 41912 ATTCTTCTGGCATGCCTAAA  75 1649 803488 N/A N/A 42134 42153 TCATCTTATGTCTCTAACCA  68 1650 803489 N/A N/A 44968 44987 TACTTTGCTGAGTACCATCC  54 1651 803490 N/A N/A 45375 45394 AGGAAGTAACCATGTCCTCA  38 1652 803491 N/A N/A 45376 45395 AAGGAAGTAACCATGTCCTC  58 1653 803492 N/A N/A 45377 45396 AAAGGAAGTAACCATGTCCT  57 1654 803493 N/A N/A 45378 45397 AAAAGGAAGTAACCATGTCC  93 1655 803494 N/A N/A 45379 45398 TAAAAGGAAGTAACCATGTC  92 1656 803495 N/A N/A 45381 45400 ATTAAAAGGAAGTAACCATG  78 1657 803496 N/A N/A 45382 45401 TATTAAAAGGAAGTAACCAT  90 1658 803497 N/A N/A 45383 45402 GTATTAAAAGGAAGTAACCA  86 1659 803498 N/A N/A 45384 45403 GGTATTAAAAGGAAGTAACC  34 1660 803499 N/A N/A 45385 45404 AGGTATTAAAAGGAAGTAAC  50 1661 803500 N/A N/A 46126 46145 TATGTATCCAAACATGGATT  71 1662 803501 N/A N/A 46232 46251 GGTGACAAAGTCTTCATCTG  58 1663 803502 N/A N/A 46931 46950 TTTATTTGAGTCTATTTCCT  79 1664 803503 N/A N/A 48097 48116 GGGTGCATAGTCTGTAGGTA  32 1665 803504 N/A N/A 48768 48787 GGATTTCAAGAGAAAAAATC  93 1666 803505 N/A N/A 48918 48937 ATATCTTTACCATGTATATG  88 1667 803506 N/A N/A 49003 49022 TCCAAACTCAGAATGCACCA  42 1668 803507 N/A N/A 49316 49335 GTCTATGAGTAATGGCATGG  47 1669 803508 N/A N/A 49674 49693 GGATTAAAATCAATTTATCA  80 1670 803509 N/A N/A 50436 50455 AATTTCTTTTGGCTTGATAC  89 1671 803510 N/A N/A 51368 51387 TTCAAATTATGCGAATCTGA  66 1672 803511 N/A N/A 51478 51497 TTGGACATCATTTCATTTAT  48 1673 803512 N/A N/A 52070 52089 ACCTTAAAAGCCCAGGATCT  85 1674 803513 N/A N/A 52149 52168 ACTTTAAAGATGCAGAAATA  80 1675 803514 N/A N/A 52150 52169 AACTTTAAAGATGCAGAAAT  92 1676 803515 N/A N/A 52151 52170 AAACTTTAAAGATGCAGAAA 111 1677 803516 N/A N/A 52152 52171 CAAACTTTAAAGATGCAGAA  63 1678 803517 N/A N/A 52153 52172 CCAAACTTTAAAGATGCAGA  28 1679 803518 N/A N/A 52155 52174 TGCCAAACTTTAAAGATGCA  40 1680 803519 N/A N/A 52156 52175 TTGCCAAACTTTAAAGATGC  30 1681 803520 N/A N/A 52157 52176 TTTGCCAAACTTTAAAGATG  63 1682 803521 N/A N/A 52158 52177 GTTTGCCAAACTTTAAAGAT  50 1683 803522 N/A N/A 52159 52178 GGTTTGCCAAACTTTAAAGA  39 1684 803523 N/A N/A 52305 52324 CCAAATATGTTTCACCCCAG  78 1685 803524 N/A N/A 52501 52520 AGCATTTTTACAATTAAGGA  59 1686 803525 N/A N/A 53088 53107 CATACTTTAGTCTGTATTTC  69 1687 803526 N/A N/A 53538 53557 TTATTATATATCATGTTTTA  83 1688 803527 N/A N/A 53539 53558 GTTATTATATATCATGTTTT  62 1689 803528 N/A N/A 53540 53559 AGTTATTATATATCATGTTT  55 1690 803529 N/A N/A 53541 53560 CAGTTATTATATATCATGTT  55 1691 803530 N/A N/A 53542 53561 ACAGTTATTATATATCATGT  33 1692 803531 N/A N/A 53544 53563 AGACAGTTATTATATATCAT  49 1693 803532 N/A N/A 53545 53564 AAGACAGTTATTATATATCA  64 1694 803533 N/A N/A 53546 53565 AAAGACAGTTATTATATATC  80 1695 803534 N/A N/A 53547 53566 CAAAGACAGTTATTATATAT 100 1696

TABLE 22 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ ID SEQ ID SEQ ID SEQ ID LRRK2 Compound NO: 1 NO: 1 NO: 2 NO: 2 % SEQ Number Start Site Stop Site Start Site Stop Site Sequence (5′ to 3′) control ID NO 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC  20  235 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC  19  235 803535 N/A N/A 53548 53567 ACAAAGACAGTTATTATATA 107 1697 803536 N/A N/A 54011 54030 TTCCTGAGTCAGCTGGGCAC  74 1698 803537 N/A N/A 55467 55486 GTTGAGTGTAGTTGAGAAGC  49 1699 803538 N/A N/A 55699 55718 AAAGATGCTTGTCTAAAGCC  51 1700 803539 N/A N/A 55823 55842 AATAAATACTCCCTCTCTCT  89 1701 803540 N/A N/A 56181 56200 ACTAAAAAGAGTGGAAATGA  98 1702 803541 N/A N/A 57300 57319 GGCAAACATAGTACTTTATT  27 1703 803542 N/A N/A 57536 57555 TGTTGCTTGCTTAAAAGAAA  87 1704 803543 N/A N/A 59667 59686 TACTGCTCACAGATATTTAT  82 1705 803544 N/A N/A 59986 60005 CTCTTGTCAATGCCCTACAC  64 1706 803545 N/A N/A 60613 60632 GCAAAAAGGTGTTCATTCTT  71 1707 803546 N/A N/A 60625 60644 ACTTTTCACCCAGCAAAAAG 106 1708 803547 N/A N/A 60658 60677 ATGCTATTTCTATTACCCCA  58 1709 803548 N/A N/A 61404 61423 ACCTTCCTCTAAATGTTATG  87 1710 803549 N/A N/A 61573 61592 CTGTCCTGCCTTTATTTGTG  86 1711 803550 N/A N/A 62233 62252 TGTTACTTACTTGTTTGTTT 108 1712 803551 N/A N/A 63413 63432 TTGACTTCATGGTACTAACA  76 1713 803552 N/A N/A 63832 63851 CAAAGCATTCCACAACATGT  65 1714 803553 N/A N/A 63953 63972 TGCATTTTCATCAACATTAG  59 1715 803554 N/A N/A 64097 64116 TTTTTGGCATAAGACTAGTT  79 1716 803555 N/A N/A 64246 64265 TCTATGTTTTTTTAACTGGG  40 1717 803556 N/A N/A 64593 64612 CAACAGTAGGAATAGCAATA  98 1718 803557 N/A N/A 64954 64973 GTTTGCTGAGTGATTCATTA  59 1719 803558 N/A N/A 66316 66335 AATGGTTTGACTTGAGACAC  52 1720 803559 N/A N/A 66412 66431 AATTTTCAAAGCGCATGAAA  92 1721 803560 N/A N/A 66414 66433 TTAATTTTCAAAGCGCATGA  45 1722 803561 N/A N/A 66415 66434 GTTAATTTTCAAAGCGCATG  29 1723 803562 N/A N/A 66416 66435 TGTTAATTTTCAAAGCGCAT  29 1724 803563 N/A N/A 66418 66437 TATGTTAATTTTCAAAGCGC  32 1725 803564 N/A N/A 66419 66438 ATATGTTAATTTTCAAAGCG  96 1726 803565 N/A N/A 66420 66439 AATATGTTAATTTTCAAAGC  90 1727 803566 N/A N/A 66421 66440 GAATATGTTAATTTTCAAAG 100 1728 803567 N/A N/A 66422 66441 TGAATATGTTAATTTTCAAA 112 1729 803568 N/A N/A 66672 66691 AGAATGCTCATGTACTGCTG  43 1730 803569 N/A N/A 66673 66692 CAGAATGCTCATGTACTGCT  55 1731 803570 N/A N/A 66911 66930 CTGTCACAACTTCTATCTAG  69 1732 803571 N/A N/A 67066 67085 GTTTCTTAAGTGGGATACAA  25 1733 803572 N/A N/A 67163 67182 ACTTAAAATGTTTTAGACCT  88 1734 803573 N/A N/A 68270 68289 AATACCTCAGCAGATGCTGA  81 1735 803574 N/A N/A 68715 68734 CACATTACTAAAACTGACTT  78 1736 803575 N/A N/A 68989 69008 AAACCAGTGTTCTAAGCTTC  64 1737 803576 N/A N/A 70079 70098 AAATGATACTAACTGCAAAC  85 1738 803577 N/A N/A 70083 70102 AAGAAAATGATACTAACTGC  78 1739 803578 N/A N/A 70146 70165 TAATCTGCATATGGGTTTCT  36 1740 803579 N/A N/A 70615 70634 AGATTATTAAATTATCATAA 112 1741 803580 N/A N/A 71056 71075 TATTTGAATTTCATGTTTCA  54 1742 803581 N/A N/A 71205 71224 TTTTTATGGAGACCGCTGGA  77 1743 803582 N/A N/A 71512 71531 GTCCATTCCCTTTGTAAAAT  53 1744 803583 N/A N/A 71525 71544 TGGAAATTTCACAGTCCATT  30 1745 803584 N/A N/A 72654 72673 TCATTAACCAAACTACTTTT 106 1746 803585 N/A N/A 72790 72809 ATTATGAGGATAAAAGAAAA 125 1747 803586 N/A N/A 72791 72810 AATTATGAGGATAAAAGAAA 121 1748 803587 N/A N/A 72792 72811 CAATTATGAGGATAAAAGAA 117 1749 803588 N/A N/A 72793 72812 CCAATTATGAGGATAAAAGA  92 1750 803589 N/A N/A 72794 72813 CCCAATTATGAGGATAAAAG  49 1751 803590 N/A N/A 72796 72815 AACCCAATTATGAGGATAAA  81 1752 803591 N/A N/A 72797 72816 GAACCCAATTATGAGGATAA  60 1753 803592 N/A N/A 72798 72817 AGAACCCAATTATGAGGATA  85 1754 803593 N/A N/A 72799 72818 AAGAACCCAATTATGAGGAT  99 1755 803594 N/A N/A 72800 72819 TAAGAACCCAATTATGAGGA  89 1756 803595 N/A N/A 73940 73959 AGATCTGTTTCCATTGCCTG  24 1757 803596 N/A N/A 74241 74260 CTTTAAGTTACACATTATTT  44 1758 803597 N/A N/A 74300 74319 CAAACTATGTTATACTTTAA  92 1759 803598 N/A N/A 76344 76363 ACTCTTCAGAGTCTGAAAAG  79 1760 803599 N/A N/A 76345 76364 AACTCTTCAGAGTCTGAAAA  71 1761 803600 N/A N/A 76346 76365 AAACTCTTCAGAGTCTGAAA  71 1762 803601 N/A N/A 76347 76366 CAAACTCTTCAGAGTCTGAA  67 1763 803602 N/A N/A 76348 76367 TCAAACTCTTCAGAGTCTGA  62 1764 803603 N/A N/A 76350 76369 TGTCAAACTCTTCAGAGTCT  20 1765 803604 N/A N/A 76351 76370 GTGTCAAACTCTTCAGAGTC  16 1766 803605 N/A N/A 77606 77625 ATAGTTGGGAACGAATAGTA  61 1767 803606 N/A N/A 77607 77626 TATAGTTGGGAACGAATAGT  89 1768 803607 N/A N/A 77608 77627 TTATAGTTGGGAACGAATAG  94 1769 803608 N/A N/A 77609 77628 CTTATAGTTGGGAACGAATA  72 1770 803609 N/A N/A 77610 77629 TCTTATAGTTGGGAACGAAT  65 1771 803610 N/A N/A 77612 77631 TGTCTTATAGTTGGGAACGA  36 1772 803611 N/A N/A 77613 77632 ATGTCTTATAGTTGGGAACG  32 1773

TABLE 23 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ ID SEQ ID SEQ ID SEQ ID LRRK2 Compound NO: 1 NO: 1 NO: 2 NO: 2 % SEQ Number Start Site Stop Site Start Site Stop Site Sequence (5′ to 3′) control ID NO 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 12  235 780254 4111 4130 86606 86625 GTTTCATTCGGTTATAAGGC 11  235 780617 N/A N/A 81581 81600 GTTTGAAGGAATAGCTGACA 35  667 87838 87857 780618 N/A N/A 81584 81603 AGTGTTTGAAGGAATAGCTG 25  668 87841 87860 780619 N/A N/A 81587 81606 CATAGTGTTTGAAGGAATAG 62  669 87844 87863 780620 N/A N/A 81590 81609 AGCCATAGTGTTTGAAGGAA 11  670 87847 87866 780621 N/A N/A 81593 81612 AAAAGCCATAGTGTTTGAAG 55  671 87850 87869 780622 N/A N/A 81596 81615 CTAAAAAGCCATAGTGTTTG 69  672 87853 87872 780623 N/A N/A 81599 81618 ATTCTAAAAAGCCATAGTGT 45  673 87856 87875 780624 N/A N/A 81630 81649 GCAGCATCATGCAAGCAGCA 12  674 87887 87906 780625 N/A N/A 81633 81652 ATTGCAGCATCATGCAAGCA 40  675 87890 87909 803612 N/A N/A 77614 77633 AATGTCTTATAGTTGGGAAC 36 1774 803613 N/A N/A 77615 77634 GAATGTCTTATAGTTGGGAA 45 1775 803614 N/A N/A 77616 77635 AGAATGTCTTATAGTTGGGA 30 1776 803615 N/A N/A 78807 78826 TAAGGACAGAGACCGAGTTT 58 1777 803616 N/A N/A 79332 79351 CATTTACATGGGATTATTTT 56 1778 803617 N/A N/A 79675 79694 ATAGCTATTATACCTCACCT 52 1779 803618 N/A N/A 79976 79995 ATTGTTAAGAAGGAAATGCA 70 1780 803619 N/A N/A 80327 80346 ACTCTGGTATATTTTATGAT N/A 1781 803620 N/A N/A 80378 80397 AGAGATTGGGAAACATTCAG 38 1782 803621 N/A N/A 80523 80542 TATAGCAAAACAACTATGAA 84 1783 803622 N/A N/A 81353 81372 CCCCAAAATTTCACTCAAAC 55 1784 803623 N/A N/A 81582 81601 TGTTTGAAGGAATAGCTGAC 50 1785 87839 87858 803624 N/A N/A 81583 81602 GTGTTTGAAGGAATAGCTGA 39 1786 87840 87859 803625 N/A N/A 81585 81604 TAGTGTTTGAAGGAATAGCT 48 1787 87842 87861 803626 N/A N/A 81586 81605 ATAGTGTTTGAAGGAATAGC 48 1788 87843 87862 803627 N/A N/A 81588 81607 CCATAGTGTTTGAAGGAATA 26 1789 87845 87864 803628 N/A N/A 81589 81608 GCCATAGTGTTTGAAGGAAT 12 1790 87846 87865 803629 N/A N/A 81591 81610 AAGCCATAGTGTTTGAAGGA 19 1791 87848 87867 803630 N/A N/A 81592 81611 AAAGCCATAGTGTTTGAAGG 34 1792 87849 87868 803631 N/A N/A 81594 81613 AAAAAGCCATAGTGTTTGAA 56 1793 87851 87870 803632 N/A N/A 81595 81614 TAAAAAGCCATAGTGTTTGA 76 1794 87852 87871 803633 N/A N/A 81597 81616 TCTAAAAAGCCATAGTGTTT 58 1795 87854 87873 803634 N/A N/A 81598 81617 TTCTAAAAAGCCATAGTGTT 71 1796 87855 87874 803635 N/A N/A 81625 81644 ATCATGCAAGCAGCATTTTA 63 1797 803636 N/A N/A 81626 81645 CATCATGCAAGCAGCATTTT 82 1798 803637 N/A N/A 81627 81646 GCATCATGCAAGCAGCATTT 23 1799 803638 N/A N/A 81628 81647 AGCATCATGCAAGCAGCATT 25 1800 803639 N/A N/A 81629 81648 CAGCATCATGCAAGCAGCAT 34 1801 803640 N/A N/A 81631 81650 TGCAGCATCATGCAAGCAGC 16 1802 87888 87907 803641 N/A N/A 81632 81651 TTGCAGCATCATGCAAGCAG 31 1803 87889 87908 803642 N/A N/A 81634 81653 CATTGCAGCATCATGCAAGC 44 1804 87891 87910 803643 N/A N/A 81635 81654 TCATTGCAGCATCATGCAAG 43 1805 87892 87911 803644 N/A N/A 81822 81841 GGAGATAATAACAGTGGCTA 48 1806 803645 N/A N/A 82500 82519 GTGGAAGTATTAAGGCTACT 14 1807 803646 N/A N/A 82501 82520 AGTGGAAGTATTAAGGCTAC 23 1808 803647 N/A N/A 82502 82521 TAGTGGAAGTATTAAGGCTA 20 1809 803648 N/A N/A 82503 82522 TTAGTGGAAGTATTAAGGCT 36 1810 803649 N/A N/A 82504 82523 TTTAGTGGAAGTATTAAGGC 43 1811 803650 N/A N/A 82506 82525 TGTTTAGTGGAAGTATTAAG 32 1812 803651 N/A N/A 82507 82526 TTGTTTAGTGGAAGTATTAA 81 1813 803652 N/A N/A 82508 82527 ATTGTTTAGTGGAAGTATTA 60 1814 803653 N/A N/A 82509 82528 TATTGTTTAGTGGAAGTATT 62 1815 803654 N/A N/A 82510 82529 TTATTGTTTAGTGGAAGTAT 36 1816 803655 N/A N/A 82697 82716 TTGTCATAGTTAAGTAACAG 20 1817 803656 N/A N/A 83102 83121 AAACAAGTAATACAGTATAC 83 1818 803657 N/A N/A 83213 83232 ATTTCAGATTTACAACAGAG 70 1819 803658 N/A N/A 85777 85796 TGTTAAAGCTTGATAATAGG 49 1820 803659 N/A N/A 86988 87007 AGCACCAAATTGTTCCTAAC 62 1821 803660 N/A N/A 89783 89802 AGCACACATAATCTATATAA 34 1822 803661 N/A N/A 89916 89935 TACCATCTATCATCAATAAA 26 1823 803662 N/A N/A 90146 90165 TTCTCTGACAACAATGACAA 62 1824 803663 N/A N/A 90678 90697 TGTCTGCACAGACACCTGTT 87 1825 803664 N/A N/A 91038 91057 GTATCTCTTAACCCAGAGAA 37 1826 803665 N/A N/A 91039 91058 TGTATCTCTTAACCCAGAGA 17 1827 803666 N/A N/A 91040 91059 ATGTATCTCTTAACCCAGAG 24 1828 803667 N/A N/A 91041 91060 CATGTATCTCTTAACCCAGA 36 1829 803668 N/A N/A 91042 91061 TCATGTATCTCTTAACCCAG 37 1830 803669 N/A N/A 91044 91063 TTTCATGTATCTCTTAACCC 26 1831 803670 N/A N/A 91045 91064 TTTTCATGTATCTCTTAACC 58 1832 803671 N/A N/A 91046 91065 GTTTTCATGTATCTCTTAAC 20 1833 803672 N/A N/A 91047 91066 TGTTTTCATGTATCTCTTAA 36 1834 803673 N/A N/A 91048 91067 CTGTTTTCATGTATCTCTTA 21 1835 803674 N/A N/A 91144 91163 AAATTAACTTGGTCTTTTTC 68 1836 803675 N/A N/A 91456 91475 TCTGTTGCTCTTAGAATCTA 23 1837 803676 N/A N/A 91530 91549 ATGGAACCTTGAACTTGGGA 25 1838 803677 N/A N/A 92329 92348 GATTCAGAAACACTTTTATA 59 1839 803678 N/A N/A 92773 92792 AAGTTGCTTTGAGAATTTTC 48 1840 803679 N/A N/A 93235 93254 AAATCTAGTCCAACTTCCTC 78 1841

TABLE 24 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ ID SEQ ID SEQ ID SEQ ID LRRK2 Compound NO: 1 NO: 1 NO: 2 NO: 2 % SEQ Number Start Site Stop Site Start Site Stop Site Sequence (5′ to 3′) control ID NO 780254 4111 4130  86606  86625 GTTTCATTCGGTTATAAGGC  18  235 780254 4111 4130  86606  86625 GTTTCATTCGGTTATAAGGC  20  235 803680 N/A N/A  93932  93951 ACTCATTGGTAATGGATTAT  24 1842 803681 N/A N/A  94454  94473 TTGCAATGTTTCAATATGCT  53 1843 803682 N/A N/A  94455  94474 ATTGCAATGTTTCAATATGC  26 1844 803683 N/A N/A  94456  94475 GATTGCAATGTTTCAATATG  58 1845 803684 N/A N/A  94457  94476 TGATTGCAATGTTTCAATAT  65 1846 803685 N/A N/A  94458  94477 CTGATTGCAATGTTTCAATA  53 1847 803686 N/A N/A  94460  94479 TGCTGATTGCAATGTTTCAA  24 1848 803687 N/A N/A  94461  94480 TTGCTGATTGCAATGTTTCA  57 1849 803688 N/A N/A  94462  94481 ATTGCTGATTGCAATGTTTC  59 1850 803689 N/A N/A  94463  94482 AATTGCTGATTGCAATGTTT  54 1851 803690 N/A N/A  94464  94483 TAATTGCTGATTGCAATGTT  75 1852 803691 N/A N/A  95362  95381 AATCGGAAATTTAAATTATC 104 1853 803692 N/A N/A  95619  95638 TTAGTGACCTAACAGCTCGG  64 1854 803693 N/A N/A  97048  97067 GTACAGTATTTATTGAATCA  27 1855 803694 N/A N/A  97142  97161 ATTTATGCTATCATGTAGTT  71 1856 803695 N/A N/A  97748  97767 AATAATATATTCCCAGGAAA  90 1857 803696 N/A N/A  97935  97954 TAGCAACCATGTGGCCTAGA  59 1858 803697 N/A N/A  98088  98107 ACTGTCAAAATCTGAAAGAT  92 1859 803698 N/A N/A  98337  98356 AGTTAGTTTGACAATTAAAA  72 1860 803699 N/A N/A  98486  98505 AGTAACTATACACATAAAGT  99 1861 803700 N/A N/A  99619  99638 CACCGGATTTGCTCTTTTTT  30 1862 803701 N/A N/A 100073 100092 AATCTACTGCACACAACACA  89 1863 803702 N/A N/A 100118 100137 AATGGAGCCATTAATTATTA  95 1864 803703 N/A N/A 100281 100300 ATTTCCTTACCTTTTCTACA 103 1865 803704 N/A N/A 100353 100372 GCTTTAAGGTAAAGTTTTTT  33 1866 803705 N/A N/A 100816 100835 GCCAGCATTCAAACCCTCAA  39 1867 803706 N/A N/A 102479 102498 ATGAGAGTAGATTTTAATAG  85 1868 803707 N/A N/A 102841 102860 CTGAGTTCCAAAGCATTTAA  80 1869 803708 N/A N/A 103029 103048 CACATTTTAATGCAGGAAAA  97 1870 803709 N/A N/A 105168 105187 TGGATATAAGTGAATACACA  71 1871 803710 N/A N/A 105655 105674 ATAGTGGCCCCTAAATCCTT  83 1872 803711 N/A N/A 105656 105675 TATAGTGGCCCCTAAATCCT  79 1873 803712 N/A N/A 105657 105676 ATATAGTGGCCCCTAAATCC  73 1874 803713 N/A N/A 105658 105677 CATATAGTGGCCCCTAAATC  88 1875 803714 N/A N/A 105659 105678 TCATATAGTGGCCCCTAAAT  80 1876 803715 N/A N/A 105661 105680 AGTCATATAGTGGCCCCTAA  46 1877 803716 N/A N/A 105662 105681 TAGTCATATAGTGGCCCCTA  58 1878 803717 N/A N/A 105663 105682 ATAGTCATATAGTGGCCCCT  57 1879 803718 N/A N/A 105664 105683 CATAGTCATATAGTGGCCCC  49 1880 803719 N/A N/A 105665 105684 CCATAGTCATATAGTGGCCC  35 1881 803720 N/A N/A 105789 105808 CTTCCAACTCATTCTCTCTC  75 1882 803721 N/A N/A 105839 105858 GTGGCCTCAGAGCTTTCTGC  62 1883 803722 N/A N/A 105902 105921 TCCACTGTGTAGCCTCATTT 103 1884 803723 N/A N/A 106062 106081 AAGCCACATTTATTACCTTT  49 1885 803724 N/A N/A 106724 106743 GAGAAATAACACAAAACTTT 101 1886 803725 N/A N/A 106922 106941 GGCACTGAAAAGTCCCAAGT  28 1887 803726 N/A N/A 107295 107314 AGTAGGAAATAGGATAAGCA  79 1888 803727 N/A N/A 108334 108353 TTAACATGTAAGGACTGAAA  97 1889 803728 N/A N/A 108377 108396 TGATGACATATCCACCACAT  84 1890 803729 N/A N/A 108774 108793 TTTAGCTTACTACTATATAT  91 1891 803730 N/A N/A 109150 109169 TAATGCAAGTAATACAAAAA 102 1892 803731 N/A N/A 109281 109300 TTCTTTAACAATCAATAGAG  79 1893 803732 N/A N/A 109893 109912 TATGGATGAAAAGTGAACAT  91 1894 803733 N/A N/A 110855 110874 GAAATTACCTACACATTAAA 103 1895 803734 N/A N/A 110955 110974 GACATTTTTAATGTACTAAT  63 1896 803735 N/A N/A 111205 111224 AATTTTCTATCCTGGAAAAG  95 1897 803736 N/A N/A 111262 111281 AGAAGGAGTTAAGTTAGCTC  51 1898 803737 N/A N/A 112344 112363 CAGTGTAGTCATACTAACAG  58 1899 803738 N/A N/A 112345 112364 ACAGTGTAGTCATACTAACA  54 1900 803739 N/A N/A 112346 112365 CACAGTGTAGTCATACTAAC  58 1901 803740 N/A N/A 112347 112366 ACACAGTGTAGTCATACTAA  31 1902 803741 N/A N/A 112348 112367 CACACAGTGTAGTCATACTA  38 1903 803742 N/A N/A 112350 112369 TGCACACAGTGTAGTCATAC  35 1904 803743 N/A N/A 112351 112370 GTGCACACAGTGTAGTCATA  30 1905 803744 N/A N/A 112352 112371 AGTGCACACAGTGTAGTCAT  27 1906 803745 N/A N/A 112353 112372 CAGTGCACACAGTGTAGTCA  19 1907 803746 N/A N/A 112354 112373 ACAGTGCACACAGTGTAGTC  45 1908 803747 N/A N/A 112629 112648 CTTGCTTTATGGTAAGAATG  46 1909 803748 N/A N/A 113302 113321 CAAGTCTGGATCACACTTGT  71 1910 803749 N/A N/A 113398 113417 AAAATTTGATCAGGGAAATG 102 1911 803750 N/A N/A 113772 113791 GTGGAATAGTGATGAATCCC  35 1912 803751 N/A N/A 113824 113843 AGACTATTTAAAAAATGGGA  77 1913 803752 N/A N/A 114604 114623 CACAGTAATTCTGAAGGCTT  64 1914 803753 N/A N/A 114621 114640 CCTTCCCCTACTGTCAACAC  80 1915 803754 N/A N/A 114658 114677 CCCCAGGCACTGTTTTCCTT  92 1916 803755 N/A N/A 115071 115090 GTTTCAGAGAACTAGAATAA  65 1917 803756 N/A N/A 115110 115129 ACTTCATCAGAAACTGCTGG  48 1918

TABLE 25 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ ID SEQ ID SEQ ID SEQ ID LRRK2 Compound NO: 1 NO: 1 NO: 2 NO: 2 % SEQ Number Start Site Stop Site Start Site Stop Site Sequence (5′ to 3′) control ID NO 780254 4111 4130  86606  86625 GTTTCATTCGGTTATAAGGC  24  235 780254 4111 4130  86606  86625 GTTTCATTCGGTTATAAGGC  26  235 803757 N/A N/A 117459 117478 AAAATTCTGATTTCCAACTC  94 1919 803758 N/A N/A 118016 118035 GTATGTTAAATAAGAATTGA  99 1920 803759 N/A N/A 118692 118711 CAATGTGATGCTTGCATTTT  87 1921 803760 N/A N/A 118987 119006 TGACACCAAATTAGTCATTT  55 1922 803761 N/A N/A 119091 119110 TGTACTCAAACATGTATATA  75 1923 803762 N/A N/A 119108 119127 GGTCACGGCCAGCCCCCTGT  95 1924 803763 N/A N/A 119608 119627 AACATACACTTTGAAGTGTT  62 1925 803764 N/A N/A 119902 119921 GTTTAGGAGAGACTATAGAA  73 1926 803765 N/A N/A 119903 119922 GGTTTAGGAGAGACTATAGA  42 1927 803766 N/A N/A 119904 119923 TGGTTTAGGAGAGACTATAG  43 1928 803767 N/A N/A 119905 119924 ATGGTTTAGGAGAGACTATA  43 1929 803768 N/A N/A 119906 119925 TATGGTTTAGGAGAGACTAT  49 1930 803769 N/A N/A 119908 119927 CATATGGTTTAGGAGAGACT  28 1931 803770 N/A N/A 119909 119928 GCATATGGTTTAGGAGAGAC   8 1932 803771 N/A N/A 119910 119929 TGCATATGGTTTAGGAGAGA  14 1933 803772 N/A N/A 119911 119930 TTGCATATGGTTTAGGAGAG  40 1934 803773 N/A N/A 119912 119931 GTTGCATATGGTTTAGGAGA  21 1935 803774 N/A N/A 120040 120059 TCTATGGAATTTCATCCTTT  62 1936 803775 N/A N/A 120380 120399 CAGCAAAACCAGGAAGTCAG  75 1937 803776 N/A N/A 121866 121885 GTATTGTTGCCAAATGAATG  50 1938 803777 N/A N/A 121867 121886 TGTATTGTTGCCAAATGAAT  64 1939 803778 N/A N/A 121868 121887 ATGTATTGTTGCCAAATGAA  66 1940 803779 N/A N/A 121869 121888 AATGTATTGTTGCCAAATGA  77 1941 803780 N/A N/A 121870 121889 CAATGTATTGTTGCCAAATG  56 1942 803781 N/A N/A 121872 121891 TTCAATGTATTGTTGCCAAA  49 1943 803782 N/A N/A 121873 121892 GTTCAATGTATTGTTGCCAA  21 1944 803783 N/A N/A 121874 121893 TGTTCAATGTATTGTTGCCA  43 1945 803784 N/A N/A 121875 121894 ATGTTCAATGTATTGTTGCC  38 1946 803785 N/A N/A 121876 121895 AATGTTCAATGTATTGTTGC  57 1947 803786 N/A N/A 122268 122287 CACATCCTTTTACAATAGTT  46 1948 803787 N/A N/A 123076 123095 AGGATGGAGACATCGAATTT  67 1949 803788 N/A N/A 123077 123096 AAGGATGGAGACATCGAATT  78 1950 803789 N/A N/A 123078 123097 GAAGGATGGAGACATCGAAT  45 1951 803790 N/A N/A 123079 123098 GGAAGGATGGAGACATCGAA  46 1952 803791 N/A N/A 123080 123099 TGGAAGGATGGAGACATCGA  67 1953 803792 N/A N/A 123082 123101 GTTGGAAGGATGGAGACATC  65 1954 803793 N/A N/A 123083 123102 AGTTGGAAGGATGGAGACAT  54 1955 803794 N/A N/A 123084 123103 GAGTTGGAAGGATGGAGACA  67 1956 803795 N/A N/A 123085 123104 AGAGTTGGAAGGATGGAGAC  82 1957 803796 N/A N/A 123086 123105 AAGAGTTGGAAGGATGGAGA  99 1958 803797 N/A N/A 124014 124033 TGGATAGACAGAAAGTTATC  89 1959 803798 N/A N/A 124460 124479 TCCAGGACAGTGTTTTAAAA  57 1960 803799 N/A N/A 125043 125062 AATCTTCATTGTAGAGAAAA  96 1961 803800 N/A N/A 125214 125233 GCGGATTTTTTAAAAAGCCT  44 1962 803801 N/A N/A 126287 126306 TAAAAAGAGACCCAAATAAC 108 1963 803802 N/A N/A 126714 126733 TTTAATTCTGTCTCTGTGTG  88 1964 803803 N/A N/A 127951 127970 GCTTGAGAAGACCTAAGTAA  72 1965 803804 N/A N/A 128819 128838 GATGGTAACCTAAATTAAAA  87 1966 803805 N/A N/A 129120 129139 AGAGCTGTGACATGGCCACC  74 1967 803806 N/A N/A 129202 129221 TCTCTAGATTCTGTTTTTGA  97 1968 803807 N/A N/A 129512 129531 CTGGAACCCAACTAGATCAC  78 1969 803808 N/A N/A 129985 130004 TGATTCTAAAGCAAAACACA  96 1970 803809 N/A N/A 130212 130231 CTTGCCTGGCAGTGGGAAAA 120 1971 803810 N/A N/A 130229 130248 AATGAAAGACTGGCTCCCTT 103 1972 803811 N/A N/A 130358 130377 GTTCAGAGATGTGCTATTTA  61 1973 803812 N/A N/A 130530 130549 GCACAATATTTATCTTCAGG  44 1974 803813 N/A N/A 130540 130559 TAATGTTGAGGCACAATATT 121 1975 803814 N/A N/A 132624 132643 AAAGATCTGTAATTTCCCCA  59 1976 803815 N/A N/A 134408 134427 AGCAATACAAATACAGCATA  55 1977 803816 N/A N/A 136673 136692 GTAGGTAGACCAATGTAGAG  73 1978 803817 N/A N/A 137059 137078 ATTAATAAAATACCTAGGAG 110 1979 803818 N/A N/A 137783 137802 TACTAAGATTACAATGAGTT  82 1980 803819 N/A N/A 137934 137953 TTCCTACAATCAATACTTAA  86 1981 803820 N/A N/A 138184 138203 GAACTATGATTTATGCTCTT  47 1982 803821 N/A N/A 138715 138734 ATTGCATCAGATTGATGTAC  82 1983 803822 N/A N/A 139321 139340 AAAAATCCTCATTCATGGGA  66 1984 803823 N/A N/A 139750 139769 TAAAGCATCTATGCTCCAAA  47 1985 803824 N/A N/A 140044 140063 GCAGACCTAGAACTCCAAAA  39 1986 803825 N/A N/A 140485 140504 AACAACGAGGAATATGTAAA  91 1987 803826 N/A N/A 140731 140750 CAAAATAGACCAACCAGTCC  87 1988 803827 N/A N/A 140958 140977 CATCCAAACATAAACAGAAA  85 1989 803828 N/A N/A 141091 141110 GTTAGCCTTTTATACCTAGA  29 1990 803829 N/A N/A 141151 141170 ATCTGTAACTTTTGAATGTT  77 1991 803830 N/A N/A 142094 142113 GGTCTTGATCCCCACTCCTT 110 1992 803831 N/A N/A 142406 142425 TATCAAGGAGACCTGTTGGC 114 1993 803832 N/A N/A 142595 142614 AAGTTTTACATGAAGTCTCA  92 1994 803833 N/A N/A 144471 144490 AGCTGTTATGGGAACCCAAA  60 1995

TABLE 26 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ ID SEQ ID SEQ ID SEQ ID LRRK2 Compound NO: 1 NO: 1 NO: 2 NO: 2 % SEQ Number Start Site Stop Site Start Site Stop Site Sequence (5′ to 3′) control ID NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  24  222 803625 N/A N/A  81585  81604 TAGTGTTTGAAGGAATAGCT  69 1787  87842  87861 876008   62   81   3181   3200 CGTCCGCTGCTCAGGGAACC  39 1996 876032  737  756  18636  18655 AACGCACTTAACAATATCAT  33 1997 876056  872  891  21703  21722 ATAGCTTCCACCACAATATT  71 1998 876080 1337 1356  31053  31072 TTTGATGAAGAATGCATCAG  83 1999 876104 1486 1505  35433  35452 CACTTTCAGCCACTTCAGGA  47 2000 876128 1728 1747  41961  41980 AATATCATTCTTGAAACACT  44 2001 876152 2493 2512  62114  62133 ATCCAGGGCCAGCCTCCTTA  76 2002 876176 3158 3177  73694  73713 TGAAGCTCCAGCTTTTCAAG  45 2003 876200 3571 3590  77320  77339 TCTCCACTTTAGGACAAGCC  35 2004 876224 3856 3875  82201  82220 GATGCAGTTTCTCTACTCTA  24 2005 876248 4319 4338  87223  87242 GGATGAGTACTATAGAATTC  41 2006 876272 4754 4773  92177  92196 TTCCGGTCAATTACGGGAAA  63 2007 876296 5075 5094  98223  98242 ATCTGGAATTTTTCTAGGAG  49 2008 876320 5482 5501 100471 100490 CAGGAAACCATTCTTCCATG  44 2009 876344 5833 5852 106524 106543 GTTTATTAAAAATCTTCACA  76 2010 876368 6603 6622 129748 129767 AATGCTTGCATTCCTGCTGT  70 2011 876392 7223 7242 141584 141603 TCCACAACAGGGCTATTTTG  75 2012 876416 8192 8211 146361 146380 AATTCATTTGAATATTTACA  89 2013 876440 9043 9062 147212 147231 GTTAAAGCATAGCTTCCTTT  63 2014 876464 N/A N/A   4983   5002 AATGAAGGTGGCCAGAATCA 125 2015 876488 N/A N/A   7242   7261 AAGTGAGTATTAAAATGTCA 112 2016 876512 N/A N/A   9238   9257 CAAAATGTAAGTTATCAGAA 138 2017 876536 N/A N/A  12445  12464 TCAATAATGTTTAGTTAGTT  85 2018 876560 N/A N/A  15299  15318 ACTATAGTACATGTATCTCA  68 2019 876584 N/A N/A  17431  17450 TTATACATGACAGCCTGAAG 121 2020 876608 N/A N/A  19744  19763 AGAACACTTATTACATACCA  56 2021 876632 N/A N/A  21991  22010 TTTTTGACACTCCTTTTAAA  93 2022 876656 N/A N/A  25071  25090 ACGATCATTCCTTATTATTC  52 2023 876680 N/A N/A  27616  27635 GGCACGACAATATTCATTGT  68 2024 876704 N/A N/A  30008  30027 CAACCTGCTGGCTAGTCACC  40 2025 876728 N/A N/A  32100  32119 TAATTATACAAAGCTATAAG 126 2026 876752 N/A N/A  33547  33566 ATAGAACATTTTACACACTA  63 2027 876776 N/A N/A  35959  35978 AACCGCCAGCTATATAATCT  73 2028 876800 N/A N/A  38194  38213 AGGTGATAACAGATGTCAGT 104 2029 876824 N/A N/A  39985  40004 AGTAATAGATTGAAAGAAAC  90 2030 876848 N/A N/A  42029  42048 TTAATAGTATAAATACAGAA 119 2031 876872 N/A N/A  45638  45657 CCGACTGCTGAGGTTACACC  64 2032 876896 N/A N/A  47955  47974 GTGAGGGAGAGGACATAAAG  99 2033 876920 N/A N/A  49786  49805 TGTATTACATAGGTATGACT  52 2034 876944 N/A N/A  52148  52167 CTTTAAAGATGCAGAAATAA 100 2035 876968 N/A N/A  55095  55114 TTACCCGTGCATGCACCTGT 119 2036 876992 N/A N/A  57336  57355 ATATTAAATACAGTAAGGTT 115 2037 877016 N/A N/A  60029  60048 CCATTCACTCCTTACTTTGT  66 2038 877040 N/A N/A  62799  62818 AAAGATAAAAATAGTGTCAG  91 2039 877064 N/A N/A  65735  65754 CTCAAGTTTTTCCAGATGAT  55 2040 877088 N/A N/A  67068  67087 AGGTTTCTTAAGTGGGATAC  40 2041 877112 N/A N/A  70290  70309 GCTTAGAGACAAATTAAGGG  37 2042 877136 N/A N/A  72623  72642 TTATATATAAATTCGAAAGA 158 2043 877160 N/A N/A  73942  73961 TCAGATCTGTTTCCATTGCC  31 2044 877184 N/A N/A  75823  75842 CAATTTCTAATTTTATAATG 111 2045 877208 N/A N/A  78402  78421 ATTTCCTCTATTATTTCATA  47 2046 877239 N/A N/A  83094  83113 AATACAGTATACAGGCCAGT  32 2047 877263 N/A N/A  85311  85330 CATTACCTTTCTTGATTTAT  85 2048 877287 N/A N/A  88256  88275 TTTCCTTTCCCATCTTCATG  92 2049 877311 N/A N/A  90591  90610 GAGGACAAAAAATGATCTCT  70 2050 877335 N/A N/A  92465  92484 CTAAATTTGTTTTCTTATGA 129 2051 877359 N/A N/A  94743  94762 ACCAGGGAGGCAATATAGAA  62 2052 877383 N/A N/A  96119  96138 CCACATGGAGAAGCACCAAT  62 2053 877407 N/A N/A  99047  99066 AAAGTCAATGAAGGTAATCA  56 2054 877431 N/A N/A 101670 101689 ATTAAGGCAAATACAAAGAT 127 2055 877455 N/A N/A 104228 104247 GCTGCATTAATATGGAGTAT  47 2056 877479 N/A N/A 106092 106111 TGCCCTTCCAACTCAATCAC  82 2057 877503 N/A N/A 108922 108941 TTATAGATAAAACTTGAAGA 126 2058 877527 N/A N/A 111504 111523 ATGCTTTAAACTGTGATTGC  72 2059 877551 N/A N/A 113499 113518 TTAAGATGATGGGTTCTAGA  77 2060 877575 N/A N/A 116118 116137 TGCAAGAAACACAAGTTGGA 102 2061 877599 N/A N/A 118373 118392 ATGCACAGGAAATCTTATTC  96 2062 877623 N/A N/A 120463 120482 ATATTGGAGATTAAAAGGGA 121 2063 877647 N/A N/A 122643 122662 TTTACAAACGACATAATCCT 117 2064 877671 N/A N/A 126280 126299 AGACCCAAATAACGATTTAA  55 2065 877695 N/A N/A 128683 128702 CCAAATCAAGAGCTCACAAC  91 2066 877719 N/A N/A 133235 133254 TAGTACTTTTTTTCCAATAC  65 2067 877743 N/A N/A 136955 136974 AGATATTCATGCTCACAGAC 142 2068 877767 N/A N/A 140322 140341 TGTTGTCAGAGAGCCACTAC  71 2069 877791 N/A N/A 141782 141801 GAAGCATTACAAATTTTTTT 105 2070 877815 N/A N/A 144092 144111 CCAAAGTACATACAATTCAA  61 2071

TABLE 27 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ ID SEQ ID SEQ ID SEQ ID LRRK2 Compound NO: 1 NO: 1 NO: 2 NO: 2 % SEQ Number Start Site Stop Site Start Site Stop Site Sequence (5′ to 3′) control ID NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  29  222 803626 N/A N/A  81586  81605 ATAGTGTTTGAAGGAATAGC  50 1788  87843  87862 876009  191 210   3310   3329 TTTCCTTCCTGGACATTGTT  50 2072 876033  738 757  18637  18656 TAACGCACTTAACAATATCA  31 2073 876057  874 893  21705  21724 TCATAGCTTCCACCACAATA  74 2074 876081 1342 1361  31058  31077 CTTCCTTTGATGAAGAATGC  39 2075 876105 1487 1506  35434  35453 CCACTTTCAGCCACTTCAGG  55 2076 876129 1865 1884  52779  52798 GAATCCATAGCACCTTCCAG  62 2077 876153 2532 2551  62153  62172 TATACAAAATCCTCCAAGGC  71 2078 876177 3198 3217  73734  73753 TTCACATAGCTGTTGTGGAA  76 2079 876201 3576 3595  77325  77344 GAAACTCTCCACTTTAGGAC  30 2080 876225 3857 3876  82202  82221 AGATGCAGTTTCTCTACTCT  43   81 876249 4320 4339  87224  87243 GGGATGAGTACTATAGAATT  44 2081 876273 4755 4774  92178  92197 TTTCCGGTCAATTACGGGAA  48 2082 876297 5077 5096  98225  98244 CAATCTGGAATTTTTCTAGG  67 2083 876321 5522 5541 100511 100530 AGAGTTTCTCCTTCACCACA  42 2084 876345 5875 5894 N/A N/A AAAGCACCACAAGCTCTTGT   18* 2085 876369 6605 6624 129750 129769 CAAATGCTTGCATTCCTGCT  61 2086 876393 7263 7282 141624 141643 TATTAGTCCACAGAGTTTTT 108 2087 876417 8267 8286 146436 146455 GAAGTTGTGTAAGATGCACT  83 2088 876441 9084 9103 147253 147272 GAGCTCTATTATATATGATT  68 2089 876465 N/A N/A   5078   5097 TTATCTAGACCCTGCAGACC 105 2090 876489 N/A N/A   7262   7281 GAAGGAAAAATACTACTTTT  92 2091 876513 N/A N/A   9756   9775 AGTTTTAGAGGTTGTACCAA  62 2092 876537 N/A N/A  12772  12791 GTAGTGGGCCGGTGGCCGTT  77 2093 876561 N/A N/A  15455  15474 GCTTAATTGCTCTACAGTCC  48 2094 876585 N/A N/A  17472  17491 ATCCTAATTGTCATCGAAAG  99 2095 876609 N/A N/A  19783  19802 ATAAAATACATATTGTCTAA  97 2096 876633 N/A N/A  22053  22072 TATAGAACTACATCTATAAA 103 2097 876657 N/A N/A  25245  25264 TACAAGTTGCTACAATGGAG  69 2098 876681 N/A N/A  27636  27655 ATGTCATGTCTGTGACACAC  65 2099 876705 N/A N/A  30159  30178 TTATGATGTTTGAATGGCAC 108 2100 876729 N/A N/A  32279  32298 ATTTTTTGCCCTCTAAAAAT 109 2101 876753 N/A N/A  33681  33700 CCCAGCAAATGCTGCTGGTC  96 2102 876777 N/A N/A  36087  36106 TGTGCCAATTATTTTTTTTA  84 2103 876801 N/A N/A  38237  38256 AATACAGACATAGGTGTTTT  86 2104 876825 N/A N/A  40148  40167 TTCTTAAAGAATTTCACATT 111 2105 876849 N/A N/A  42157  42176 TTTCACTTCCCACATCCCCA  91 2106 876873 N/A N/A  45665  45684 CACAGCACTTACTTGCTCTC  45 2107 876897 N/A N/A  48048  48067 AATTCCAGGAACCACAAACT  98 2108 876921 N/A N/A  49975  49994 TCAGTACAGGTTAATGATGA  63 2109 876945 N/A N/A  52174  52193 CAGCTTCATGTAATAGGTTT  44 2110 876969 N/A N/A  55241  55260 CCTCTAATATTACATATTAA 111 2111 876993 N/A N/A  57372  57391 AATCCATAGGCAAGTGGGAT  63 2112 877017 N/A N/A  60530  60549 ACCATTTCTCCTCCCGGCTC  83 2113 877041 N/A N/A  62800  62819 AAAAGATAAAAATAGTGTCA 136 2114 877065 N/A N/A  65802  65821 TTCCTTGACCCATCACTTTA  87 2115 877089 N/A N/A  67069  67088 AAGGTTTCTTAAGTGGGATA  60 2116 877113 N/A N/A  70299  70318 TGGCCTTCTGCTTAGAGACA  36 2117 877137 N/A N/A  72643  72662 ACTACTTTTTATAACTAAAT 150 2118 877161 N/A N/A  73943  73962 ATCAGATCTGTTTCCATTGC  36 2119 877185 N/A N/A  76014  76033 TTTGAATTAATGATTTAACA 128 2120 877209 N/A N/A  78477  78496 GAATTCCTGTTTATTGTCAT  64 2121 877240 N/A N/A  83109  83128 AGCTGAAAAACAAGTAATAC 112 2122 877264 N/A N/A  85425  85444 AATTAGAGAAAAAGACTAAA 117 2123 877288 N/A N/A  88395  88414 AAGAAAAGAACAACTGTCCT  75 2124 877312 N/A N/A  90592  90611 AGAGGACAAAAAATGATCTC  86 2125 877336 N/A N/A  92591  92610 ACATTATGAATGTCATTTGA 111 2126 877360 N/A N/A  94819  94838 TCCTGATTAACATTCTTTAA  76 2127 877384 N/A N/A  96218  96237 ATCTGCTTCATTTCTCTTGG  60 2128 877408 N/A N/A  99066  99085 GCAAATGATTTTACTGCTTA  52 2129 877432 N/A N/A 101696 101715 CTTATTTGCCTCCCATATCC 112 2130 877456 N/A N/A 104260 104279 TTTTTAAAGCCCTTCTCTAT 110 2131 877480 N/A N/A 106129 106148 CTACACTTCCAACTTTGTGT  97 2132 877504 N/A N/A 108958 108977 GAAACCTGTAAGAGACAGTC 111 2133 877528 N/A N/A 111524 111543 GTGTGATGTTAAATTGATTC  58 2134 877552 N/A N/A 113529 113548 CATTTTTATAGAAGGCAGAT  68 2135 877576 N/A N/A 116214 116233 ACTCTCCTACTAGACTGTAA  69 2136 877600 N/A N/A 118773 118792 ATTCTCTTCTTTTTATTCAG  64 2137 877624 N/A N/A 120519 120538 ATTAGGCCCTGGGTTTCTGA  87 2138 877648 N/A N/A 122804 122823 AAGATAAAACATATCCCTAA  83 2139 877672 N/A N/A 126378 126397 TTTATGTAAATTTACTTGTC 108 2140 877696 N/A N/A 128758 128777 TAAAGTCATTATAGTTGTAC  83 2141 877720 N/A N/A 133258 133277 AAAAAACAGGCTTCACATTT 127 2142 877744 N/A N/A 137015 137034 ATCTCTATAAGGAAACCTGA 120 2143 877768 N/A N/A 140412 140431 TTTAACAATCATTAGTATAT  88 2144 877792 N/A N/A 141884 141903 GAGAACATTCTTTGTAATAC  66 2145 877816 N/A N/A 144288 144307 TGAGAAGAACTGGATGTTCA  65 2146

TABLE 28 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ ID SEQ ID SEQ ID SEQ ID LRRK2 Compound NO: 1 NO: 1 NO: 2 NO: 2 % SEQ Number Start Site Stop Site Start Site Stop Site Sequence (5′ to 3′) control ID NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  38  222 780619 N/A N/A  81587  81606 CATAGTGTTTGAAGGAATAG  91  669  87844  87863 876010  304  323   3695   3714 AGACGATCAACAGAGGCACA  56 2147 876034  740  759  18639  18658 GTTAACGCACTTAACAATAT  46 2148 876058  875  894  21706  21725 TTCATAGCTTCCACCACAAT  72 2149 876082 1403 1422 N/A N/A TTTCTGAAATTAACATTTTG  88 2150 876106 1489 1508  35436  35455 AGCCACTTTCAGCCACTTCA  41 2151 876130 1867 1886  52781  52800 CTGAATCCATAGCACCTTCC  55 2152 876154 2537 2556  62158  62177 TTTCCTATACAAAATCCTCC  55 2153 876178 3212 3231 N/A N/A AAACTCTTCAGAGTTTCACA 108 2154 876202 3615 3634 N/A N/A CAAGAAAGGCATAGCAGCAA  77 2155 876226 3858 3877  82203  82222 AAGATGCAGTTTCTCTACTC 105 2156 876250 4383 4402  87287  87306 TTCAGCCTGTCCCTTGCTGA  91 2157 876274 4757 4776  92180  92199 CGTTTCCGGTCAATTACGGG  32 2158 876298 5151 5170  99157  99176 GGGAAGCTCTATCACAGGCC  31 2159 876322 5543 5562 100532 100551 TATAATGCCCATTTCTTCAA  99 2160 876346 5880 5899 113077 113096 GTGGCAAAGCACCACAAGCT  35 2161 876370 6606 6625 129751 129770 CCAAATGCTTGCATTCCTGC  73 2162 876394 7324 7343 142972 142991 TTTTGTGTTTTGATTCCTTG  65 2163 876418 8308 8327 146477 146496 TTTCATTAGTACTTTTAATG 120 2164 876442 9131 9150 147300 147319 AAATTGCAAATACAAAGTAA 137 2165 876466 N/A N/A   5103   5122 CTGGGTTGTCAAGTATAGCA  81 2166 876490 N/A N/A   7469   7488 TATCATGTTAAATGGCATCT  56 2167 876514 N/A N/A   9834   9853 CATATAATTTCTAAATTATG 126 2168 876538 N/A N/A  12900  12919 GTTGATATATTAAAATATAG 101 2169 876562 N/A N/A  15482  15501 ATTCTCATCTAGAATGCAAA  93 2170 876586 N/A N/A  17692  17711 TACTCTACATTTATAGTCAT 117 2171 876610 N/A N/A  19865  19884 GAAGGCTCACACCTTCAGAT  72 2172 876634 N/A N/A  22186  22205 TATACAACATTTAAGTTGGA  95 2173 876658 N/A N/A  25650  25669 CATCTGTGTATAAATATGTA  85 2174  25680  25699  25710  25729  25740  25759  25804  25823  25868  25887 876682 N/A N/A  27649  27668 CTGATTCCCTCTCATGTCAT  63 2175 876706 N/A N/A  30201  30220 ACTCCTTGCTACAGCTTGTA  40 2176 876730 N/A N/A  32460  32479 GGTGAGATGAAAAAGGAGGA  64 2177 876754 N/A N/A  33697  33716 CTGTTTATCAAGTTCCCCCA  61 2178 876778 N/A N/A  36104  36123 GTTTTCACTGCAACTTCTGT  73 2179 876802 N/A N/A  38252  38271 TAAATGTGTTGGATGAATAC 104 2180 876826 N/A N/A  40280  40299 TAGAGTTTCATATCCCTTTG  58 2181 876850 N/A N/A  42247  42266 GAGTGGATTTATGTTACTGG  35 2182 876874 N/A N/A  45671  45690 CCACATCACAGCACTTACTT  60 2183 876898 N/A N/A  48092  48111 CATAGTCTGTAGGTAGTAGT  54 2184 876922 N/A N/A  50209  50228 CGTTAATAATTTTCAAACAA 145 2185 876946 N/A N/A  52275  52294 CTTGACCAGTAAAACGCAAT  72 2186 876970 N/A N/A  55359  55378 CAGAGTCTGTCCTCTTCACT  79 2187 876994 N/A N/A  57490  57509 GTTTATGTGATTTTAATTCA  60 2188 877018 N/A N/A  60774  60793 AAGCACTACAGAGCTCTGAT  75 2189 877042 N/A N/A  63004  63023 CTGACCAAAACTGGTGTTTT 131 2190 877066 N/A N/A  65861  65880 TTTCCTGGAATATTAACCAT  57 2191 877090 N/A N/A  67071  67090 AAAAGGTTTCTTAAGTGGGA  70 2192 877114 N/A N/A  70300  70319 CTGGCCTTCTGCTTAGAGAC  55 2193 877138 N/A N/A  72664  72683 ATATAATTTCTCATTAACCA  79 2194 877162 N/A N/A  73945  73964 TAATCAGATCTGTTTCCATT  52 2195 877186 N/A N/A  76016  76035 TATTTGAATTAATGATTTAA 155 2196 877210 N/A N/A  78507  78526 TATTCTCTATGAAGGAAGAT  72 2197 877241 N/A N/A  83229  83248 GACAAACAAATTATCAATTT  70 2198 877265 N/A N/A  86490  86509 TCTTTTACATGTCACACTAT 116 2199 877289 N/A N/A  88459  88478 TGTTGATATTTGCTTTCCGT  45 2200 877313 N/A N/A  90605  90624 TGAAAAATAAATGAGAGGAC 107 2201 877337 N/A N/A  92763  92782 GAGAATTTTCATCTTTGAGA  42 2202 877361 N/A N/A  94894  94913 TTATTTGTCCCCATACATGA 102 2203 877385 N/A N/A  96275  96294 GTAGCAGAATTAATATTTTT  59 2204 877409 N/A N/A  99079  99098 CCAACCTTGTTGAGCAAATG 109 2205 877433 N/A N/A 101710 101729 CACCTGAAAACTGTCTTATT 123 2206 877457 N/A N/A 104825 104844 ACTGGAATCAGAAATAGAAT 119 2207 877481 N/A N/A 106421 106440 AATTAAGCTGTCCAAGCGAA 150 2208 877505 N/A N/A 109331 109350 TGAATGTGAAGAATGCCCAT  97 2209 877529 N/A N/A 111530 111549 TAGCTTGTGTGATGTTAAAT  56 2210 877553 N/A N/A 113596 113615 GACTCATCTTTCCTCATTGG  52 2211 877577 N/A N/A 116216 116235 TGACTCTCCTACTAGACTGT  66 2212 877601 N/A N/A 118774 118793 CATTCTCTTCTTTTTATTCA  60 2213 877625 N/A N/A 120524 120543 AAAAGATTAGGCCCTGGGTT  71 2214 877649 N/A N/A 122888 122907 ATTATACATTTCCTTAGAAT 142 2215 877673 N/A N/A 126380 126399 TATTTATGTAAATTTACTTG 115 2216 877697 N/A N/A 128864 128883 ATTTTTACTGTGGACATAAA  96 2217 877721 N/A N/A 133263 133282 GGTACAAAAAACAGGCTTCA  55 2218 877745 N/A N/A 137032 137051 AACAAAGATGATGAACGATC 134 2219 877769 N/A N/A 140492 140511 ATGAATGAACAACGAGGAAT 145 2220 877793 N/A N/A 141955 141974 TGTGACAGAACTATGTCAAA  87 2221 877817 N/A N/A 144304 144323 AATATAGCATAGTAATTGAG 109 2222

TABLE 29 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ ID SEQ ID SEQ ID SEQ ID LRRK2 Compound NO: 1 NO: 1 NO: 2 NO: 2 % SEQ Number Start Site Stop Site Start Site Stop Site Sequence (5′ to 3′) control ID NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  32  222 803627 N/A N/A  81588  81607 CCATAGTGTTTGAAGGAATA  47 1789  87845  87864 876011  309  328   3700   3719 GTCCAAGACGATCAACAGAG  47 2223 876035  797  816  18696  18715 AGGGAATGTAAACAATGCAG  41 2224 876059  876  895  21707  21726 TTTCATAGCTTCCACCACAA  59 2225 876083 1408 1427 N/A N/A GTATTTTTCTGAAATTAACA  87 2226 876107 1490 1509  35437  35456 CAGCCACTTTCAGCCACTTC  49 2227 876131 1952 1971  52992  53011 TTCTTTGTAATCAAGTATCC 110 2228 876155 2558 2577  62179  62198 CCAAGCCAAGAAGGTTCAAC  51 2229 876179 3214 3233 N/A N/A TCAAACTCTTCAGAGTTTCA  97 2230 876203 3620 3639 80900  80919 GGAGGCAAGAAAGGCATAGC  46 2231 876227 3860 3879  82205  82224 GAAAGATGCAGTTTCTCTAC  59 2232 876251 4388 4407  87292  87311 TCAACTTCAGCCTGTCCCTT 105 2233 876275 4781 4800  92204  92223 TTTTCTCTCACTAGTTGTAA  48 2234 876299 5191 5210  99197  99216 TTTCATATAGTCGGATGATA  72 2235 876323 5566 5585 100555 100574 GTTCTTCACCATCATTAAAA  61 2236 876347 5979 5998 113176 113195 AAGCAGGCGATCCAAGGAAC 112 2237 876371 6645 6664 129790 129809 AAATGAGAGCTGTCCTCTGT  71 2238 876395 7354 7373 143002 143021 AGAGGGTTTTCACTCTCCCA  60 2239 876419 8313 8332 146482 146501 TGTTTTTTCATTAGTACTTT  91 2240 876443 9170 9189 147339 147358 AATATGGTATTCATTTTTTT 100 2241 876467 N/A N/A   5161   5180 ATGCTCAGGCTTGGGCAATT  64 2242 876491 N/A N/A   7474   7493 TGGAATATCATGTTAAATGG  65 2243 876515 N/A N/A  10519  10538 AAATAAATACTCAAGGCCAT  88 2244 876539 N/A N/A  13003  13022 TATTTTCACCCAACTCCATA 126 2245 876563 N/A N/A  15487  15506 TTTGCATTCTCATCTAGAAT 108 2246 876587 N/A N/A  17742  17761 CCCCTGAGTCCTGGAGAACC  99 2247 876611 N/A N/A  19889  19908 ATTGGGTTTTACTCTGCCTA  41 2248 876635 N/A N/A  22443  22462 CCACATGCAAAAATATTTCT  57 2249 876659 N/A N/A  25651  25670 ACATCTGTGTATAAATATGT  61 2250  25681  25700  25711  25730  25741  25760  25805  25824  25869  25888 876683 N/A N/A  27820  27839 GATGAATATTCAATGGCATT  36 2251 876707 N/A N/A  30247  30266 AAAACACAAAGGCTCACGGA  73 2252 876731 N/A N/A  32510  32529 CTGTCAGTGCCCTGGCCACT  42 2253 876755 N/A N/A  33873  33892 GTGGCTAGCTTCTAGCCAAG 110 2254 876779 N/A N/A  36197  36216 TGTTATTATCATTCCTCTTT  95 2255 876803 N/A N/A  38423  38442 AAAGCCTTTTATATATGCAT  57 2256 876827 N/A N/A  40345  40364 CTTTTTAAGTCCTCCATATT  65 2257 876851 N/A N/A  42335  42354 AGAAAACAGCAGCCATAGTA 113 2258 876875 N/A N/A  45683  45702 AAGTGATTTTCTCCACATCA  62 2259 876899 N/A N/A  48094  48113 TGCATAGTCTGTAGGTAGTA  23 2260 876923 N/A N/A  50229  50248 TGTTGTCACCCTTGTAAAAT  85 2261 876947 N/A N/A  52382  52401 AATTCACTGAGGGTTAGAAT  82 2262 876971 N/A N/A  55369  55388 AGCACATCCCCAGAGTCTGT  76 2263 876995 N/A N/A  57777  57796 TAAATTGAAAGAATAGTAGA 147 2264 877019 N/A N/A  60820  60839 AAATGCCCACCAGTCTCCAA  93 2265 877043 N/A N/A  63105  63124 AAACCTTGATGTATAAAGGC 115 2266 877067 N/A N/A  65930  65949 TACACAAGCCACGAAAGGAT  72 2267 877091 N/A N/A  67193  67212 TCTTCATTGACACACCACAC  52 2268 877115 N/A N/A  70305  70324 TCACTCTGGCCTTCTGCTTA  76 2269 877139 N/A N/A  72670  72689 ATATCCATATAATTTCTCAT  97 2270 877163 N/A N/A  74025  74044 GAATTAAATGATTAAAGTAT  91 2271 877187 N/A N/A  76071  76090 TTTTGTAAATTATTTCCAGA  80 2272 877211 N/A N/A  78563  78582 AAAAATTATTTTACTGAGTC 158 2273 877242 N/A N/A  83232  83251 TGAGACAAACAAATTATCAA  55 2274 877266 N/A N/A  86571  86590 CGCTGTTGAAGAAACCTAGT  62 2275 877290 N/A N/A  88524  88543 GAGCCTGGAGGGAAAGACAC  99 2276 877314 N/A N/A  90620  90639 GATCAAAGGCAAATATGAAA  81 2277 877338 N/A N/A  92815  92834 ATTTCTAGCAAGGTAATATG  82 2278 877362 N/A N/A  94924  94943 GTACAGGATGCAGCTACCTA  56 2279 877386 N/A N/A  96286  96305 GTTACTAGAATGTAGCAGAA  74 2280 877410 N/A N/A  99359  99378 CATCTCCCTAATTTCTCTAA  92 2281 877434 N/A N/A 101744 101763 GTCATTTTATAAAATATGGC  95 2282 877458 N/A N/A 104836 104855 AACTGTTACATACTGGAATC 109 2283 877482 N/A N/A 106589 106608 ATGTGCAATTTAATATAATT  89 2284 877506 N/A N/A 109785 109804 ACTTGTGGCCCACAGGTCGC  87 2285 877530 N/A N/A 111542 111561 TGTTGAAATGTATAGCTTGT  57 2286 877554 N/A N/A 113660 113679 GACATGTGAGATGGTCATGC  55 2287 877578 N/A N/A 116500 116519 TCTTCATAGCTTAAAGTAAA  79 2288 877602 N/A N/A 118817 118836 GAATCTACAAATCTAACTTT 118 2289 877626 N/A N/A 120677 120696 AAAATTGGAGGCAGAGTTTA  94 2290 877650 N/A N/A 122924 122943 ATATTGTTACAGATACAATG  90 2291 877674 N/A N/A 126393 126412 CTCCATAATCCTATATTTAT  83 2292 877698 N/A N/A 128986 129005 AAGTATGTCTAAGCTTTTTA  59 2293 877722 N/A N/A 133331 133350 TTGAAATTTTTCTTTGACCA  36 2294 877746 N/A N/A 137262 137281 TTTCCATCTTAAATGATTAG  86 2295 877770 N/A N/A 140513 140532 AATAGAAGAAGGCACTACAG 111 2296 877794 N/A N/A 142230 142249 AAATAAAAATATAAAGTGGC 154 2297 877818 N/A N/A 144312 144331 TGAGGCAAAATATAGCATAG  93 2298

TABLE 30 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ ID SEQ ID SEQ ID SEQ ID LRRK2 Compound NO: 1 NO: 1 NO: 2 NO: 2 % SEQ Number Start Site Stop Site Start Site Stop Site Sequence (5′ to 3′) control ID NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  43  222 780620 N/A N/A  81590  81609 AGCCATAGTGTTTGAAGGAA  28  670  87847  87866 876013  339  358   3730 3749 CTGCTGCACACTCGCGACTC  55 2299 876037  821  840 N/A N/A TCCACATTATTGCAAGGAAT  51 2300 876061  930  949  21761  21780 CCTATGGAGCAAACAGCAAC  89 2301 876085 1455 1474  35402  35421 CTTCTGCATTAACTCCAAAA  49 2302 876109 1493 1512  35440  35459 TTACAGCCACTTTCAGCCAC  33 2303 876133 2042 2061  53082  53101 TTAGTCTGTATTTCAGCAAC  81 2304 876157 2626 2645  65464  65483 TTCTTGCTAGTGTAGATGCT  48 2305 876181 3216 3235 N/A N/A TGTCAAACTCTTCAGAGTTT  40 2306 876205 3703 3722 N/A N/A AAGACCGCAAGTGTGGAAGA  56 2307 876229 3929 3948  83924  83943 CTGACATCCAGAGATGTCAG  89 2308 876253 4432 4451 N/A N/A AAGAAGCGCGAGCCTTTATA 103 2309 876277 4877 4896  93338  93357 AACTGCAGTGCTGGGTCTTG  49 2310 876301 5194 5213  99200  99219 GCATTTCATATAGTCGGATG  22 2311 876325 5610 5629 100599 100618 TTCCTCTGCTTTCTTCATCA  56 2312 876349 6023 6042 113220 113239 ATCCTGTGCTGTAGGGTTCT  58 2313 876373 6689 6708 N/A N/A TCAGCAACTTCCTCAGAAGT  97 2314 876397 7400 7419 143048 143067 TGGCCTCCTCCAGTTCCTAT  73 2315 876421 8402 8421 146571 146590 CTATTATGTCTAGGAAAGAC 138 2316 876445 N/A N/A   3487   3506 CTCCTTAAGAGTCCGGGTTT 103 2317 876469 N/A N/A   5188   5207 TGACACTCATAACTACTCCG  68 2318 876493 N/A N/A   7785   7804 AATACAATTAAATTGGTAGT  97 2319 876517 N/A N/A  10746  10765 AAAATCTACAACTTAACCAG 107 2320 876541 N/A N/A  13064  13083 AAAAAGTTAAAAGCACTACT  90 2321 876565 N/A N/A  15570  15589 CTTTAAGAATATCTCCTACA  97 2322 876589 N/A N/A  17908  17927 AGTGATCAACATTCATTTTT  58 2323 876613 N/A N/A  19993  20012 TTATTGTTCAGCCCCACCCA  92 2324 876637 N/A N/A  22715  22734 CTATCCTGTGAACAATATTG  74 2325 876661 N/A N/A  25662  25681 TATATTTATATACATCTGTG  60 2326  25692  25711  25722  25741  25752  25771  25816  25835  25880  25899 876685 N/A N/A  27910  27929 AGTTAAGTGAAACATTAGCT  98 2327 876709 N/A N/A  30373  30392 AACAAATAGACGGTCAAGAT  58 2328 876733 N/A N/A  32619  32638 TCCCTGTCCAGACCTCTTTA  83 2329 876757 N/A N/A  33996  34015 ATACTGCCAGAGCCTGAAAA  81 2330 876781 N/A N/A  36419  36438 TTAGTTAGACTGATGTTAAA  96 2331 876805 N/A N/A  38456  38475 GAAGAAATTATTTGTGCCTC  56 2332 876829 N/A N/A  40740  40759 GAGGTCCTACTATTCAAATG  49 2333 876853 N/A N/A  42906  42925 CTTCTCTTTTTCATACTCAG  47 2334 876877 N/A N/A  46382  46401 AGAAGACTGGTTTTACTTTA  78 2335 876901 N/A N/A  48096  48115 GGTGCATAGTCTGTAGGTAG  28 2336 876925 N/A N/A  50288  50307 TTCACAGGTGTGTATTTCAC  62 2337 876949 N/A N/A  52569  52588 AAATCAGTATCCTTGATTTT  92 2338 876973 N/A N/A  55733  55752 GGAAAAAGAACTAATACCCT  97 2339 876997 N/A N/A  57805  57824 AAAATCCTGTTGGGTAGAAA  84 2340 877021 N/A N/A  61061  61080 CCCTTACAGCTAGCAAGCAA  75 2341 877045 N/A N/A  63132  63151 AACTTTTGGAGCCTACTGAG  79 2342 877069 N/A N/A  66149  66168 TCATTATATATTTCACCATA  47 2343 877093 N/A N/A  67368  67387 TAAGAATAAGGTATAAATCA 114 2344 877117 N/A N/A  70856  70875 ATTTTAAATTCCCCTACTCT  87 2345 877141 N/A N/A  72684  72703 TGAGTGAAAAAGCTATATCC  52 2346 877165 N/A N/A  74316  74335 AGAGCTATCCTATCAACAAA  83 2347 877189 N/A N/A  76262  76281 CTTACACACCTCTGGTAACT  47 2348 877213 N/A N/A  78841  78860 TTTGTCTGTGCTCTGAACTT  69 2349 877244 N/A N/A  83428  83447 CCTAATTGGAGTAATTTCTT  89 2350 877268 N/A N/A  86896  86915 TCCATACAGTCTACCAGGTT  50 2351 877292 N/A N/A  89032  89051 GGCATCAAAAACATTTTCTC  23 2352 877316 N/A N/A  90814  90833 AGATGCCTGCTCTGCTAATG  83 2353 877340 N/A N/A  93050  93069 TTCACACATAAGTAGAAATT 106 2354 877364 N/A N/A  95117  95136 CTGTATAAGATATACCCATC  35 2355 877388 N/A N/A  96349  96368 TGCTATTCATATAGAGTCTC  27 2356 877412 N/A N/A  99735  99754 ATTTTGGAAACCAGTAACAC  94 2357 877436 N/A N/A 101885 101904 TTTGAGTATGTCACCATGTA  59 2358 877460 N/A N/A 104875 104894 ATTAGTTAGGATTGTTGGTA  62 2359 877484 N/A N/A 106759 106778 AGGATTCTCAGATACAGTGT  99 2360 877508 N/A N/A 109926 109945 AATCCTATGGTGAGTACCTC  94 2361 877532 N/A N/A 111674 111693 GATCCAATGGCAACAACCCT  97 2362 877556 N/A N/A 113970 113989 GGAATGTAAGGTGACTCTCA  80 2363 877580 N/A N/A 116687 116706 AGACTAGCAAAATAGCTTTT  97 2364 877604 N/A N/A 118908 118927 GTGGACCTGAATTTGATTTG  58 2365 877628 N/A N/A 120831 120850 AGGAAGATTCATTAAACGGA  76 2366 877652 N/A N/A 123128 123147 AAAGATGGAGCTCAGCAGTC  89 2367 877676 N/A N/A 126731 126750 TTTGCCTTATAACTATTTTT  92 2368 877700 N/A N/A 129195 129214 ATTCTGTTTTTGATCTGGAG  78 2369 877724 N/A N/A 133350 133369 CCTTGCCCAATTCCATCCAT  49 2370 877748 N/A N/A 138041 138060 TATTCTTGTTTGAAACTGGT  46 2371 877772 N/A N/A 140642 140661 CCCTCACACTAGATTATGAG  72 2372 877796 N/A N/A 142347 142366 AGAAAAACTGTCAGATGAAT 116 2373 877820 N/A N/A 144537 144556 ATATTCTAGTGAAGAGACTA 164 2374

TABLE 31 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ ID SEQ ID SEQ ID SEQ ID LRRK2 Compound NO: 1 NO: 1 NO: 2 NO: 2 % SEQ Number Start Site Stop Site Start Site Stop Site Sequence (5′ to 3′) control ID NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  19  222 780621 N/A N/A  81593  81612 AAAAGCCATAGTGTTTGAAG  35  671  87850  87869 876016  395  414  10419  10438 CTTTGCATTGTACCTGGACA  37 2375 876040  825  844 N/A N/A GACTTCCACATTATTGCAAG  36 2376 876064 1070 1089 N/A N/A ATAGTCTCAGTGAGGAGGGC  50 2377 876088 1468 1487  35415  35434 GAGAATGTATATGCTTCTGC  15 2378 876112 1539 1558  37588  37607 TATATCCAGGGAAGTGTTGC  71 2379 876136 2091 2110  56025  56044 AGAAAAAGATGCTGACAATT  86 2380 876160 2802 2821 N/A N/A GCCTTCACTTCCTTCACTAT  59 2381 876184 3223 3242  76357  76376 CCAAATGTGTCAAACTCTTC  39 2382 876208 3791 3810  82136  82155 TTATGGCTAAATAAGAGTTC  69 2383 876232 4012 4031  84007  84026 GATGCAGTTCATCCAAAGGA  35 2384 876256 4609 4628  88710  88729 TTTTCCGAAGTTTTGCCAAA  73 2385 876280 4967 4986  98115  98134 GGGTGTTTTGGACAACCTTC  37 2386 876304 5198 5217  99204  99223 TAAGGCATTTCATATAGTCG  48 2387 876328 5647 5666 101285 101304 TGAGCCTTGGTTGATCTGGA  21 2388 876352 6072 6091 118405 118424 AATCATGGCTGAGTGGAGGT  80 2389 876376 6738 6757 132448 132467 TTCCTTTTCAACAGGAAGAT  68 2390 876400 7495 7514 N/A N/A TTCCTAGCTGTGCTGTCATC  91 2391 876424 8539 8558 146708 146727 GAAGCAGATTAGAAAACAAG  86 2392 876448 N/A N/A   3736   3755 CTTTACCTGCTGCACACTCG  63 2393 876472 N/A N/A   5572   5591 CCAGAGACTGGAAATGAAAG  95 2394 876496 N/A N/A   7851   7870 TCCATTAATCTATTCAATTA  78 2395 876520 N/A N/A  10808  10827 GTATCGATTCTATTATTAAA  71 2396 876544 N/A N/A  13929  13948 AATCAAGCTACCCTAATCCT  95 2397 876568 N/A N/A  15860  15879 TAAATGAGATAAACTCCCAG  96 2398 876592 N/A N/A  18000  18019 TATTGGGCAACAACCTGAAA  95 2399 876616 N/A N/A  20210  20229 TTTTAGCTGCTACTTTCTTG  84 2400 876640 N/A N/A  23220  23239 GATACATAAAAAAGAGTAAA 135 2401 876664 N/A N/A  26207  26226 AGATTAAAACATTATCAGAT  84 2402 876688 N/A N/A  28199  28218 ACAACTGTTAGTTTCCTTGA  55 2403 876712 N/A N/A  30796  30815 TTTCAAAAGCATATGCAGCA  51 2404 876736 N/A N/A  32794  32813 CAGTCGAAATTTCACAAAGT  66 2405 876760 N/A N/A  34084  34103 CTTAAGTACTGCTTTTAAAA  69 2406 876784 N/A N/A  36835  36854 CCTCCCCTCCTTGGGTAACC  93 2407 876808 N/A N/A  38630  38649 TCAGCCTTTCCTTCCACACT  74 2408 876832 N/A N/A  40891  40910 TATTACACCTTAAGAAGATG 106 2409 876856 N/A N/A  42932  42951 TTACACAATTTAAATGTAAT 104 2410 876880 N/A N/A  46724  46743 TTAGTTCCAGAAAATACTAT  71 2411 876904 N/A N/A  48100  48119 CCAGGGTGCATAGTCTGTAG  44 2412 876928 N/A N/A  50374  50393 CTTCTACAAAAAAAAGTCAG  87 2413 876952 N/A N/A  52953  52972 CACTGAATTTCTAGGAAAAT 117 2414 876976 N/A N/A  56393  56412 AGAATACTGAGCAAAGACAA  88 2415 877000 N/A N/A  58100  58119 GTCTAACACAACTCCACCCT  95 2416 877024 N/A N/A  61215  61234 CCAAGATAACAGGTAATAGA  60 2417 877048 N/A N/A  63290  63309 CTTCCAGACTGGTGATAGCA  97 2418 877072 N/A N/A  66302  66321 AGACACAATATTTTGGAACA  53 2419 877096 N/A N/A  67753  67772 GTTAGAAATTTTAAAAGACT  86 2420 877120 N/A N/A  71190  71209 CTGGAATAGGGTCTAGCAGC  37 2421 877144 N/A N/A  72946  72965 AAAAATGGGCCCCTATTAAA 102 2422 877168 N/A N/A  74838  74857 TCCCTTAAATATACTTAAAA 101 2423 877192 N/A N/A  76677  76696 GTTGTTAAAACTCATTGCTA  38 2424 877216 N/A N/A  79254  79273 GACCACTTCTCAAACTATTA  64 2425 877247 N/A N/A  83670  83689 CTCCCAAACAATCTATGTCA  41 2426 877271 N/A N/A  87005  87024 AACCGATCAAAGTACCTAGC  36 2427 877295 N/A N/A  89220  89239 CACAGTGACAAAATTCATGA  50 2428 877319 N/A N/A  91037  91056 TATCTCTTAACCCAGAGAAT  79 2429 877343 N/A N/A  93174  93193 CTGGGACTAGAAGCTGTGCA  37 2430 877367 N/A N/A  95220  95239 ACTTAATTACTCCACAGAAT  91 2431 877391 N/A N/A  96751  96770 TTCTCTCATTTGAATATCAG  63 2432 877415 N/A N/A  99949  99968 TAAAAAGAGTTAAATCCCCT  88 2433 877439 N/A N/A 102322 102341 TGTACAAAGTATATCTTTTT  45 2434 877463 N/A N/A 104975 104994 ATTAGATTGTAAATATGTTA 147 2435 877487 N/A N/A 106908 106927 CCAAGTTTCTACATTTCTAA  64 2436 877511 N/A N/A 110185 110204 TTGTTGAGAAAAGCACAGAT  94 2437 877535 N/A N/A 111992 112011 CATTGGCATTCATTCAATCC  73 2438 877559 N/A N/A 114281 114300 GGTATCTGCAAGGAACCTCA  87 2439 877583 N/A N/A 117201 117220 TTCAATTGTATGAGGGCCTG 102 2440 877607 N/A N/A 119250 119269 TTACTTCCTGCTCAAACTGA  99 2441 877631 N/A N/A 121200 121219 CAGGAGCTCTGCTCTCAGGC  67 2442 877655 N/A N/A 123752 123771 GTACTACTCTTTCTTTCTTT  62 2443 877679 N/A N/A 126891 126910 TTTTTTCTGATTTGATTTGT  81 2444 877703 N/A N/A 129329 129348 GCATGCAATTCTATATTGCA 100 2445 877727 N/A N/A 133490 133509 CCCACTTCCTTCCAACAAGG  77 2446 877751 N/A N/A 138235 138254 GAAAGGTTATTGCCCAAGTT  45 2447 877775 N/A N/A 140814 140833 GCCACATCAGCATGGCAAAC  50 2448 877799 N/A N/A 142668 142687 TACCAAAGCTATCTAATTCA  99 2449 877823 N/A N/A 144798 144817 TTAAACGAGGTAATGTGTGT  60 2450

TABLE 32 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5’ to 3’) control NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  37  222 803631 N/A N/A  81594  81613 AAAAAGCCATAGTGTTTGAA  80 1793  87851  87870 876017  400  419  10424  10443 TTAAGCTTTGCATTGTACCT  40 2451 876041  827  846 N/A N/A AGGACTTCCACATTATTGCA  37 2452 876065 1084 1103  29345  29364 CTTGATTTAAGAAAATAGTC  83 2453 876089 1469 1488  35416  35435 GGAGAATGTATATGCTTCTG  27 2454 876113 1555 1574  37604  37623 GGACCACTGCTGCCATTATA  43 2455 876137 2130 2149  56064  56083 GAATATTACTAAGTCAAATG  84 2456 876161 2843 2862  71686  71705 CCTACACTAATTGAATTAGA  52 2457 876185 3224 3243  76358  76377 TCCAAATGTGTCAAACTCTT  31 2458 876209 3796 3815  82141  82160 TCTGATTATGGCTAAATAAG  41 2459 876233 4017 4036  84012  84031 GTTAAGATGCAGTTCATCCA  55 2460 876257 4621 4640  88722  88741 CGTTTATGATGGTTTTCCGA  79 2461 876281 5042 5061  98190  98209 GACATGTAGTTCTTTGGAAA  44 2462 876305 5199 5218  99205  99224 ATAAGGCATTTCATATAGTC  74 2463 876329 5648 5667 101286 101305 GTGAGCCTTGGTTGATCTGG  55 2464 876353 6093 6112 118426 118445 GGGTTTCAGGTCTCGGTATA  72 2465 876377 6777 6796 132487 132506 CAGGAGAGTACCAGACTGTG  71 2466 876401 7516 7535 145119 145138 CCAGCATGACATTTTTAAGG  37 2467 876425 8551 8570 146720 146739 AAGCATTAGAATGAAGCAGA  56 2468 876449 N/A N/A   3738   3757 GCCTTTACCTGCTGCACACT  69 2469 876473 N/A N/A   5806   5825 CTCTAAATTAATTACTTAAC  97 2470 876497 N/A N/A   7895   7914 TGATTAAATAGAATCTCTGG  89 2471 876521 N/A N/A  10905  10924 AAATGTACTATTTAAAGACA  84 2472 876545 N/A N/A  13978  13997 GGCTGTCCCATCACTAGGTC  40 2473 876569 N/A N/A  15888  15907 GTTAGACTTATCAAGCTCTA  41 2474 876593 N/A N/A  18037  18056 TTTGATCAAGCCAGTAAGTT  47 2475 876617 N/A N/A  20433  20452 TGTTTAAAAAAAGGCTGTTT  88 2476 876641 N/A N/A  23260  23279 ATTATCTTAGGGAAAGGACA  83 2477 876665 N/A N/A  26250  26269 TGTGCTACTCTGACACCTGG  41 2478 876689 N/A N/A  28210  28229 GTATATTTGTCACAACTGTT  52 2479 876713 N/A N/A  30800  30819 GCTTTTTCAAAAGCATATGC  35 2480 876737 N/A N/A  32826  32845 TGTAACCAGTCCTCAGACAC  73 2481 876761 N/A N/A  34100  34119 ACATAAAAAGTTTTAACTTA 105 2482 876785 N/A N/A  36869  36888 AAAGTCCCAGTTTAAACACA  73 2483 876809 N/A N/A  38643  38662 TTTTCTTTGGGCCTCAGCCT 110 2484 876833 N/A N/A  40900  40919 GAGGCTGCCTATTACACCTT  60 2485 876857 N/A N/A  42939  42958 TTTTGCATTACACAATTTAA  74 2486 876881 N/A N/A  46818  46837 TGGAGTTAGGCCATATGAAT  45 2487 876905 N/A N/A  48102  48121 GTCCAGGGTGCATAGTCTGT  28 2488 876929 N/A N/A  50419  50438 TACCAGTATCTTAAATTCAG  93 2489 876953 N/A N/A  53117  53136 AGTTCCCAAATTCTTTCCAA  86 2490 876977 N/A N/A  56418  56437 AATGGCAGGGCTCTTACATT  45 2491 877001 N/A N/A  58449  58468 GAGCCACCCTGCATGAAGCT  74 2492 877025 N/A N/A  61291  61310 GCACTGCATGCTGGCCCTAC 122 2493 877049 N/A N/A  63355  63374 TTATATAATGTGGTGAATGG 124 2494 877073 N/A N/A  66309  66328 TGACTTGAGACACAATATTT  52 2495 877097 N/A N/A  67953  67972 ATTGTGAACAAAGAAAATCC 110 2496 877121 N/A N/A  71306  71325 CAAATCAATCAACGGTTACA  60 2497 877145 N/A N/A  73081  73100 TAATTGGAGGAAATTCAACC 113 2498 877169 N/A N/A  74847  74866 GAAAAAACATCCCTTAAATA 119 2499 877193 N/A N/A  77052  77071 TAAAAGTTGTAATATTCATT  88 2500 877217 N/A N/A  79613  79632 TTCAGAGTCTTGAGTTTCAT  51 2501 877248 N/A N/A  84372  84391 TCTTTAGATTGTGTAATTGG  43 2502 877272 N/A N/A  87027  87046 CACTTTTAGCATATTTGTCA  80 2503 877296 N/A N/A  89765  89784 AAATGGAACAGAACTAAGCT 100 2504 877320 N/A N/A  91067  91086 CAAATGGTTACTCAAGAGAC  68 2505 877344 N/A N/A  93198  93217 ATTTCAGCATAGCTAGTGAC 102 2506 877368 N/A N/A  95236  95255 CTTTCATGGAGTTTCAACTT 100 2507 877392 N/A N/A  96941  96960 TCCCATGTTGTGTACTTTAT  36 2508 877416 N/A N/A 100066 100085 TGCACACAACACAAGTGATT  64 2509 877440 N/A N/A 102409 102428 TCTCCATTCCACAACATATA  98 2510 877464 N/A N/A 105094 105113 ATGGAAAGCCTCTACCTATT 111 2511 877488 N/A N/A 106972 106991 TGGAGGCAGCTAGGAGTCTG 100 2512 877512 N/A N/A 110233 110252 CAAAGGCCTAAAGCCAATTA 128 2513 877536 N/A N/A 112047 112066 AGGCCTTCCAGACCTTCTCG 108 2514 877560 N/A N/A 114295 114314 GATATAAAGCCTCTGGTATC  98 2515 877584 N/A N/A 117209 117228 CCTGAACTTTCAATTGTATG  73 2516 877608 N/A N/A 119259 119278 CTAAATGATTTACTTCCTGC  77 2517 877632 N/A N/A 121414 121433 TGCCATAGGACCCAGAATTA 146 2518 877656 N/A N/A 124006 124025 CAGAAAGTTATCAAATATGT  90 2519 877680 N/A N/A 126954 126973 AGCTCGAAAAAGAAATTGCA  80 2520 877704 N/A N/A 129393 129412 TAACTTGAAAAGAAAATCTC 105 2521 877728 N/A N/A 133512 133531 CCTAATCACATTGACAACTG 101 2522 877752 N/A N/A 138252 138271 GAGATGACTGAAGATGTGAA  73 2523 877776 N/A N/A 140877 140896 TTTCCCTTTCAACCTAAGAC  99 2524 877800 N/A N/A 142754 142773 CTTTACTTGAAGCATAAATT  93 2525 877824 N/A N/A 144813 144832 CCCAAAGTTACAATGTTAAA  72 2526

TABLE 33 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5’ to 3’) control NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  38  222 780622 N/A N/A  81596  81615 CTAAAAAGCCATAGTGTTTG  53  672  87853  87872 876019  486  505  13752  13771 ACTGGCATTATGAACTGTTA  37 2527 876043  829  848  21660  21679 TGAGGACTTCCACATTATTG  47 2528 876067 1156 1175  29417  29436 CTTCCAGCCAAAACAATTTA  99 2529 876091 1472 1491  35419  35438 TCAGGAGAATGTATATGCTT  47 2530 876115 1613 1632  37662  37681 GCCTCCAGCTGCACTGGTAA  58 2531 876139 2223 2242  56231  56250 GTAATCATCCATAGCTACTT  31 2532 876163 2867 2886  71710  71729 AATACGGCATCTCGGTAAAA  77 2533 876187 3227 3246  76361  76380 AAGTCCAAATGTGTCAAACT  44 2534 876211 3799 3818  82144  82163 TGATCTGATTATGGCTAAAT  49 2535 876235 4053 4072  84048  84067 GTCTTTGGCTTTACATCCTA  48 2536 876259 4697 4716  92120  92139 TTTTCAAGTTCTACATAGCA  59 2537 876283 5045 5064  98193  98212 TGTGACATGTAGTTCTTTGG  38 2538 876307 5251 5270  99257  99276 GTGAAATCTCAAGTAATCGA  74 2539 876331 5651 5670 101289  101308 ATGGTGAGCCTTGGTTGATC  57 2540 876355 6160 6179 118493 118512 TGCCGTAGTCAGCAATCTTT  86 2541 876379 6821 6840 132531 132550 TTTTCTAGGGTATGTCTCTT  88 2542 876403 7579 7598 N/A N/A AGCAAGATTGTATCTCTTTC  78 2543 876427 8599 8618 146768 146787 AATGATGTAGGATCTGCAGC  65 2544 876451 N/A N/A   3760   3779 AATGAGTTGAAGTGAAAACA  130 2545 876475 N/A N/A   6080   6099 TATCAACAGATTAACAAAGA  111 2546 876499 N/A N/A   7975   7994 TTGGTGAAGCAACAGTATCA  42 2547 876523 N/A N/A  10994  11013 TACAGATGTGCTGAAAGTTA 112 2548 876547 N/A N/A  14093  14112 TAAAACCAATGTATTGAATG  84 2549 876571 N/A N/A  16270  16289 ATAACTGTGTTCTACTTTTC  82 2550 876595 N/A N/A  18575  18594 AGACTTAAAAATGAAAGACA 106 2551 876619 N/A N/A  20584  20603 AAAATATAAGTCTTAGGGAC  89 2552 876643 N/A N/A  23603  23622 GTGCCTAAAAAAGAATGTAT  49 2553 876667 N/A N/A  26400  26419 AGTAGCATTTCCCTGATCAC  49 2554 876691 N/A N/A  29101  29120 AAAAAAAAACCTAATAGACG 118 2555 876715 N/A N/A  30926  30945 AAATATCTCTAACAACAATT  88 2556 876739 N/A N/A  33082  33101 GTAGCCATTTTTTCTAAAAA  51 2557 876763 N/A N/A  34583  34602 TAATGATTAAGGAATAATTT 124 2558 876787 N/A N/A  36936  36955 ATCAGAACCATGTTCTCACT  95 2559 876811 N/A N/A  38784  38803 CTATCATCCTCTGCACCACA  96 2560 876835 N/A N/A  41037  41056 CCCTCCTCCAACTTTCAGTC  89 2561 876859 N/A N/A  43022  43041 TATGTCTTTATTCTTAACAT  67 2562 876883 N/A N/A  47044  47063 TATTCAGCTTTCTTTGCTTT  93 2563 876907 N/A N/A  48276  48295 GATACTTTTAAATCTAATAG 116 2564 876931 N/A N/A  50755  50774 CTTCTTTTACCTCCAAACCC  81 2565 876955 N/A N/A  53306  53325 AATGGTGAATAACCATGCTG  76 2566 876979 N/A N/A  56534  56553 CCTAAAGGACCCTATTACTT  99 2567 877003 N/A N/A  59266  59285 CAGTGCCCAGGTGGTAATGA  73 2568 877027 N/A N/A  61418  61437 TCTCTCAGTCTTCAACCTTC  93 2569 877051 N/A N/A  63467  63486 ATGTGCAAAACACTAGTATC  74 2570 877075 N/A N/A  66552  66571 ATTGTCAGGAAGCAAATGAT  60 2571 877099 N/A N/A  68281  68300 TGAAAAATATGAATACCTCA 100 2572 877123 N/A N/A  71767  71786 ACAATTTAACTTACCAAGGA 152 2573 877147 N/A N/A  73109  73128 GATGAAACTGGCACCAAGAA 100 2574 877171 N/A N/A  74897  74916 GTGGGTCACCTTTCTTTCTT  43 2575 877195 N/A N/A  77106  77125 ATCAAAGAGGACTCATTAAT 116 2576 877219 N/A N/A  79825  79844 CAAATCTACCGTTTCTAGGA  84 2577 877250 N/A N/A  84428  84447 GTTAACTAGTTGCTATATGA  54 2578 877274 N/A N/A  87487  87506 ACTCGGAAAGTTTCCCAATT  63 2579 877298 N/A N/A  89963  89982 GAATAGGAAAGTCTACAAAT  72 2580 877322 N/A N/A  91301  91320 TAATATCCAGAGTGCCGTTA  52 2581 877346 N/A N/A  93489  93508 CTTAACTAAACCCAAATTCT 116 2582 877370 N/A N/A  95491  95510 TCAGACAAGTTGCTCTTGGT  31 2583 877394 N/A N/A  97213  97232 AAGAGGTTTGTATTTAATTT  68 2584 877418 N/A N/A 100658 100677 CACTTCATAAGTATTGAAGG  53 2585 877442 N/A N/A 102464 102483 AATAGTTCTCACCACATAAA 101 2586 877466 N/A N/A 105201 105220 TCTCATATAGTGCCTTGAAA  65 2587 877490 N/A N/A 107094 107113 AGTCATGTTCAATAAAAATA 124 2588 877514 N/A N/A 110289 110308 AGGTGGGAATATTCTAAGTA  48 2589 877538 N/A N/A 112191 112210 CTACAAAAGTTTACCGAGGA  67 2590 877562 N/A N/A 114372 114391 GAAAGATTCAGATAATCCTT 130 2591 877586 N/A N/A 117360 117379 ATAATTTCTCACAAGACTTA  85 2592 877610 N/A N/A 119341 119360 GTAATTTTACTTACAAATAA 101 2593 877634 N/A N/A 121663 121682 TAAGAGAAATTTATGAATTA 108 2594 877658 N/A N/A 124138 124157 AACCTAAAGACATCCAATCA  86 2595 877682 N/A N/A 127082 127101 CAACAGGACCAAATAGGAAT  78 2596 877706 N/A N/A 130011 130030 GGGACCCTGAGCTAAGACAT  99 2597 877730 N/A N/A 134153 134172 AAATGGCCTTAATGTTCTCC  71 2598 877754 N/A N/A 138408 138427 TTTGTGACTCAAAGCTAATA  76 2599 877778 N/A N/A 140926 140945 CCATTTTCCCCTTTTAAACA  79 2600 877802 N/A N/A 143250 143269 AAGACCATCCATATGACACT  89 2601 877826 N/A N/A 144863 144882 AACAGCTTAACCTTTCTATA  88 2602

TABLE 34 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5’ to 3’) control NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  44  222 876020  528  547  13794  13813 GAGGAGATCTAAGGTCTTCA  37 2603 876044  830  849  21661  21680 ATGAGGACTTCCACATTATT 110 2604 876068 1161 1180  29422  29441 ACAGGCTTCCAGCCAAAACA  15 2605 876092 1473 1492  35420  35439 TTCAGGAGAATGTATATGCT  93 2606 876116 1637 1656  37686  37705 ATAAAATGTAAAATAGCTCG  56 2607 876140 2262 2281  56270  56289 ATTCTGATCACACGCTCTCT  46 2608 876164 2869 2888  71712  71731 GTAATACGGCATCTCGGTAA  84 2609 876188 3228 3247  76362  76381 CAAGTCCAAATGTGTCAAAC  97 2610 876212 3800 3819  82145  82164 CTGATCTGATTATGGCTAAA  66 2611 876236 4144 4163  86639  86658 TTTTACCACTCCCAGTATTT  76 2612 876260 4725 4744  92148  92167 CACATTTTTACGCTCCGATA  49 2613 876284 5046 5065  98194  98213 CTGTGACATGTAGTTCTTTG  65 2614 876308 5338 5357 100190 100209 CTTCAGGAGACCAATTTAAG  75 2615 876332 5652 5671 101290 101309 AATGGTGAGCCTTGGTTGAT 126 2616 876356 6204 6223 118537 118556 GCCCTCTGATGTTTTTATCC  31 2617 876380 6826 6845 132536 132555 TCATCTTTTCTAGGGTATGT  38 2618 876404 7660 7679 145829 145848 TTTCAGCTAATTCTTTTCTC 100 2619 876428 8683 8702 146852 146871 GAAAAGTGTTAGATATTTAT  34 2620 876452 N/A N/A   3761   3780 GAATGAGTTGAAGTGAAAAC  53 2621 876476 N/A N/A   6208   6227 ATCCAGTAATCTCATCGCTG  50 2622 876500 N/A N/A   8095   8114 ATTCTGAACAGCTTCTGGTG 102 2623 876524 N/A N/A  11128  11147 TTTTCCTGGAAACACATTCT  71 2624 876548 N/A N/A  14203  14222 AAGGGCAGGAATGACCACTA 127 2625 876572 N/A N/A  16432  16451 GCAATTGAAGAAAGTCTACT  81 2626 876596 N/A N/A  18903  18922 GTTTCTCCAGCACCAAGCCC 126 2627 876620 N/A N/A  20690  20709 TTCCAGAAGGGCAACCAATG  89 2628 876644 N/A N/A  23667  23686 GAACTGGACAAGTTAATCCT  57 2629 876668 N/A N/A  26426  26445 TGCTGTTCTAGACAATTTGG  73 2630 876692 N/A N/A  29204  29223 AAGCCTTGGTCAATTATAAA 131 2631 876716 N/A N/A  30940  30959 CACTTGCCATTATCAAATAT 100 2632 876740 N/A N/A  33139  33158 TGTATGCAACCTTGGGACCT  56 2633 876764 N/A N/A  34714  34733 TGGAAAGCATTTACATAGAA  97 2634 876788 N/A N/A  36957  36976 TGTTAACTGAAACTTGTGCA  44 2635 876812 N/A N/A  38785  38804 TCTATCATCCTCTGCACCAC  52 2636 876836 N/A N/A  41061  41080 TAAGGAAGGCAGCCTTGATA  42 2637 876860 N/A N/A  43045  43064 TTTATAAAAATGTTCACACT  31 2638 876884 N/A N/A  47090  47109 AATCTCATCCATCTGTAATT  80 2639 876908 N/A N/A  48315  48334 TACTCTGATTTCCTCATCTT  66 2640 876932 N/A N/A  50766  50785 CTTTACAATGTCTTCTTTTA 103 2641 876956 N/A N/A  53309  53328 ATAAATGGTGAATAACCATG 140 2642 876980 N/A N/A  56543  56562 TGGATAACACCTAAAGGACC  39 2643 877004 N/A N/A  59276  59295 GTATTTGGAGCAGTGCCCAG  52 2644 877028 N/A N/A  61596  61615 GTACCTTAACACAGTAAATA 104 2645 877052 N/A N/A  63476  63495 TAATCTACTATGTGCAAAAC  53 2646 877076 N/A N/A  66557  66576 TCTACATTGTCAGGAAGCAA  51 2647 877100 N/A N/A  68445  68464 ATCTCTCACAGATGCAAAAT  74 2648 877124 N/A N/A  71781  71800 ATAATCACAATTGCACAATT 107 2649 877148 N/A N/A  73144  73163 GAATCATTAGGTAAATATAT 107 2650 877172 N/A N/A  74948  74967 AGTGGAGAAGAGAGAAAGAC  63 2651 877196 N/A N/A  77137  77156 TATCAAAAACAATTTGCTTT 143 2652 877220 N/A N/A  79895  79914 ACAGTCTCTTTTCTTATCTG  74 2653 877232 N/A N/A  81609  81628 TTTAGTGTCAATTCTAAAAA 101 2654 877251 N/A N/A  84464  84483 CAGTAGCTATAATGCTTTAA  66 2655 877275 N/A N/A  87627  87646 TTTAGATTTCATTTAAGAAA  69 2656 877299 N/A N/A  89982  90001 AATTACATGTCCAACAAGAG  35 2657 877323 N/A N/A  91362  91381 AATAAAAGTATCTTCCAAAC  76 2658 877347 N/A N/A  93509  93528 AAATTCACAAAAGTTTCTGC  90 2659 877371 N/A N/A  95698  95717 TTTCATATCTCTTTTATCAT  77 2660 877395 N/A N/A  97239  97258 TTTTGCTTTGTCAAATTCAC  41 2661 877419 N/A N/A 100725 100744 CTATAATTGAATATACTATT  33 2662 877443 N/A N/A 102592 102611 ATTAAATCAATCTAATGCAT 122 2663 877467 N/A N/A 105313 105332 CTCAATCCCCAAGGAGTTTG  61 2664 877491 N/A N/A 107115 107134 CTTTCACCCTGAACACACAG  72 2665 877515 N/A N/A 110361 110380 CTCAACCCTCACCCATGCAG 100 2666 877539 N/A N/A 112217 112236 CCTGCTTATAATCTCTGGTT  57 2667 877563 N/A N/A 114595 114614 TCTGAAGGCTTACTATTTTA  72 2668 877587 N/A N/A 117410 117429 ACTACAGCATTTCATGTGAT  51 2669 877611 N/A N/A 119355 119374 ATGTATAGCCACCTGTAATT  47 2670 877635 N/A N/A 121814 121833 CTTGGATAATTATCATAATG  70 2671 877659 N/A N/A 124271 124290 TCTCTTGGGTTCATGCCTGA  49 2672 877683 N/A N/A 127120 127139 TAAATATTTTTGTAGCTCTA  47 2673 877707 N/A N/A 130019 130038 TGTTTCTAGGGACCCTGAGC  66 2674 877731 N/A N/A 134194 134213 AAATGTTGAAATTGTTACAA  68 2675 877755 N/A N/A 138536 138555 AAATGACAATTAGGAGGGTC  61 2676 877779 N/A N/A 141131 141150 CTTGCAAAACTTTGTTTCAT  38 2677 877803 N/A N/A 143288 143307 AATTTATACCAGTCTTATGT 147 2678 877827 N/A N/A 144888 144907 ATTCTTAATTATGTGAGTCT  75 2679

TABLE 35 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5’ to 3’) control NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  17  222 780624 N/A N/A  81630  81649 GCAGCATCATGCAAGCAGCA  33  674  87887  87906 876021  545  564 N/A N/A ATTTTACCTGAAGTTAGGAG  71 2680 876045  831  850  21662  21681 CATGAGGACTTCCACATTAT  56 2681 876069 1229 1248  29580  29599 TTATTTAGTGCCCAGCATGC  61 2682 876093 1474 1493  35421  35440 CTTCAGGAGAATGTATATGC  41 2683 876117 1678 1697  41911  41930 ATTCTGTATCCTCCCTGGAT  49 2684 876141 2267 2286  56275  56294 CTGTTATTCTGATCACACGC  25 2685 876165 2870 2889  71713  71732 TGTAATACGGCATCTCGGTA  24 2686 876189 3229 3248  76363  76382 GCAAGTCCAAATGTGTCAAA  30 2687 876213 3801 3820  82146  82165 GCTGATCTGATTATGGCTAA  24 2688 876237 4149 4168  86644  86663 GGTGGTTTTACCACTCCCAG  31 2689 876261 4727 4746  92150  92169 GGCACATTTTTACGCTCCGA  10 2690 876285 5048 5067  98196  98215 TACTGTGACATGTAGTTCTT  18 2691 876309 5343 5362 100195 100214 ATAAGCTTCAGGAGACCAAT  51 2692 876333 5654 5673 101292 101311 GGAATGGTGAGCCTTGGTTG  42 2693 876357 6244 6263 124875 124894 CATTTCCTCTGGCAACTTCA  55 2694 876381 6856 6875 132566 132585 AATTGCAATACAAACAAGTG 115 2695 876405 7723 7742 145892 145911 ATAATTTTCCTATCCAAAGA 108 2696 876429 8688 8707 146857 146876 CAACTGAAAAGTGTTAGATA  67 2697 876453 N/A N/A   4066   4085 ATACTTGGAATAGTCAAGTC  73 2698 876477 N/A N/A   6274   6293 TAGCACAGCCATGATGAAAC  74 2699 876501 N/A N/A   8339   8358 TTGGATCTTTTCCAGATTAA  48 2700 876525 N/A N/A  11354  11373 AAAAGATTTAAAGTTAATGA 101 2701 876549 N/A N/A  14435  14454 ACTTCAGTGTTTGTCACTTA  62 2702 876573 N/A N/A  16563  16582 AATTTCTATGATTTCTGGTG  57 2703 876597 N/A N/A  19215  19234 ACTGAGCTACTTTTGTCTTC  65 2704 876621 N/A N/A  20798  20817 TTGGAGAATGACTTTTGCAT  77 2705 876645 N/A N/A  23873  23892 TGCATTTCTTTATGAAAACA  26 2706 876669 N/A N/A  26498  26517 AAAGTTACATATGACATGAC  99 2707 876693 N/A N/A  29206  29225 AGAAGCCTTGGTCAATTATA  45 2708 876717 N/A N/A  30957  30976 TAACTATCTCAAATTCTCAC  64 2709 876741 N/A N/A  33365  33384 GATGTCTAACATATCATATT  39 2710 876765 N/A N/A  34855  34874 TCACTCAGCTTTTTGGGAGT  60 2711 876789 N/A N/A  37013  37032 TTGACTAGAATGCAGTAGGT  43 2712 876813 N/A N/A  38806  38825 TGTATCTAGTCTCTCTCCCT  70 2713 876837 N/A N/A  41246  41265 ATAATGTTTTCCAAACCTAA  85 2714 876861 N/A N/A  43074  43093 CCATTAATTATTTTAAATAG 125 2715 876885 N/A N/A  47190  47209 AAATTTCCCTCCAACAAGGT  78 2716 876909 N/A N/A  48331  48350 ATATTAGAAGTGCAAATACT 102 2717 876933 N/A N/A  50793  50812 CTTTAAAATCATTCCTTTAC 143 2718 876957 N/A N/A  53340  53359 TTAGCACATTCTCTGAACTT  76 2719 876981 N/A N/A  56553  56572 AAGATTAGACTGGATAACAC  79 2720 877005 N/A N/A  59643  59662 ACATTTAAATAATAATGAAG 126 2721 877029 N/A N/A  61788  61807 ATCAATGTCAGAATAGCATG  87 2722 877053 N/A N/A  63610  63629 TGCCAAATTGTCCTCAAAAG 142 2723 877077 N/A N/A  66573  66592 CTAGAGAAAACATTAATCTA 125 2724 877101 N/A N/A  68563  68582 AAAATACCTTTACACAAATT 116 2725 877125 N/A N/A  71841  71860 TTGTTCCTAGCTTTGGCATA  93 2726 877149 N/A N/A  73151  73170 ATGGAAGGAATCATTAGGTA  47 2727 877173 N/A N/A  74967  74986 GTATTTAGCAAGGCAAAGAA  92 2728 877197 N/A N/A  77171  77190 AAATTGCATAAATTCATATG 114 2729 877221 N/A N/A  79928  79947 CTGTGAAACACAATTTGGGA  60 2730 877252 N/A N/A  84473  84492 ACATGATGTCAGTAGCTATA  41 2731 877276 N/A N/A  87718  87737 TTCACACTAAATGGCCCCTG  81 2732 877300 N/A N/A  90037  90056 TAATTGGATGAATAAATTTT 132 2733 877324 N/A N/A  91380  91399 TAAGAGGATAGTTTCTACAA  57 2734 877348 N/A N/A  93609  93628 TGGCTTGAAAACCAAGTCAT  86 2735 877372 N/A N/A  95700  95719 TCTTTCATATCTCTTTTATC  68 2736 877396 N/A N/A  97476  97495 TGATCCTTGTCATGGCAGTT  36 2737 877420 N/A N/A 100797 100816 AATCAACATTTTCTGAATCT  84 2738 877444 N/A N/A 102597 102616 TTTATATTAAATCAATCTAA 120 2739 877468 N/A N/A 105335 105354 AAGAGCTCTGCTACTCCATC 131 2740 877492 N/A N/A 107501 107520 TAAAGAACTTGAGAAGGTGA  94 2741 877516 N/A N/A 110418 110437 CCACTGTTAACTAACAGTGT 144 2742 877540 N/A N/A 112261 112280 CTATAGCCACTACTAATCAG 109 2743 877564 N/A N/A 114597 114616 ATTCTGAAGGCTTACTATTT  89 2744 877588 N/A N/A 117435 117454 TTCTCTGCCCCATGATGTCA  75 2745 877612 N/A N/A 119387 119406 GGTGATTTAATTGAGTTGCA  45 2746 877636 N/A N/A 121878 121897 TAAATGTTCAATGTATTGTT  70 2747 877660 N/A N/A 124436 124455 GAGAGATGAGTAGAAAGGAG  92 2748 877684 N/A N/A 127318 127337 GCACATTATCTTTAATAAAT  84 2749 877708 N/A N/A 130037 130056 ATAACCCATCTCAGGCTCTG  62 2750 877732 N/A N/A 134431 134450 CTACTGTGTTCAAGATTTTA  66 2751 877756 N/A N/A 138860 138879 AGCACAGATGGCAAAAAGCT  77 2752 877780 N/A N/A 141161 141180 GAAATATTATATCTGTAACT  85 2753 877804 N/A N/A 143352 143371 AATCTGCTTCTCTTGTGGGA  68 2754 877828 N/A N/A 145005 145024 CAAATACCTTGGAACTGAAT 109 2755

TABLE 36 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5’ to 3’) control NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  49  222 803643 N/A N/A  81635  81654 TCATTGCAGCATCATGCAAG  53 1805  87892  87911 876025  706  725  18605  18624 TCTCAACAAATTCAGTCAGT  55 2756 876049  836  855  21667  21686 CCACTCATGAGGACTTCCAC  55 2757 876073 1235 1254  29586  29605 AGGAGATTATTTAGTGCCCA  35 2758 876097 1478 1497  35425  35444 GCCACTTCAGGAGAATGTAT  39 2759 876121 1697 1716  41930  41949 ATATTTAGCTTATGATGAAA  93 2760 876145 2448 2467  62069  62088 ACCTTTCCCAATGCTTATCG  57 2761 876169 2890 2909  71733  71752 GCAAATTTGGTGAGCAACGC  50 2762 876193 3294 3313  76428  76447 ATCAAGATTAGCAATACAAC 105 2763 876217 3807 3826  82152  82171 CAAGATGCTGATCTGATTAT  64 2764 876241 4309 4328  87213  87232 TATAGAATTCCTCACGACCT  85 2765 876265 4732 4751  92155  92174 CAATTGGCACATTTTTACGC  79 2766 876289 5053 5072  98201  98220 TAAAATACTGTGACATGTAG  39 2767 876313 5446 5465 100435 100454 CCACAACTTGGCCCAAAAGA  68 2768 876337 5691 5710 101329 101348 GTCAGCCAAAATCAAGTCAG  48 2769 876361 6380 6399 125011 125030 GGTAATTTTCCTTGTATTTC  57 2770 876385 6998 7017 137402 137421 GGAGTACTGACATTTCCTAT  46 2771 876409 7903 7922 146072 146091 ATAAGAAATATAACATTGTG  99 2772 876433 8823 8842 146992 147011 CCTCAAATTATTACATAGGT  60 2773 876457 N/A N/A   4255   4274 TAAGACATCACTTTCTTTAG  58 2774 876481 N/A N/A   6920   6939 GAATCAAATATTGGCTGTGC 115 2775 876505 N/A N/A   8749   8768 CATATATGTACCCTCTAGAG  88 2776 876529 N/A N/A  11687  11706 CTGATACATAGAATTACAGA  70 2777 876553 N/A N/A  14518  14537 GCCAAAGTTTTCTCAGGGAA  54 2778 876577 N/A N/A  16867  16886 GGGCCCACATAAATCATTCT 113 2779 876601 N/A N/A  19369  19388 CTCTCCACTCCATGTCTCTG  75 2780 876625 N/A N/A  21104  21123 ACAATAATGTAACATATTTT  94 2781 876649 N/A N/A  24272  24291 AGCAAACATTTAAAAGCCCA  52 2782 876673 N/A N/A  26747  26766 CATAATTAGATTACATAGTT 110 2783 876697 N/A N/A  29480  29499 TTTATGAGAGTCCTACCTGC 131 2784 876721 N/A N/A  31326  31345 TAGAAGTCCGGAAAAATATA 106 2785 876745 N/A N/A  33421  33440 TCTTACTCAATAGTCACCTT  72 2786 876769 N/A N/A  35273  35292 TTAGAATATTAATATAGTCC  44 2787 876793 N/A N/A  37536  37555 ACTGATCTGATTCAATGGTA  96 2788 876817 N/A N/A  38963  38982 CAGAACAAAGTATCATCCCT  88 2789 876841 N/A N/A  41339  41358 CTTTATTAAGCTACACTGTA  82 2790 876865 N/A N/A  43282  43301 AGATAAATTTAACCCATTAC  95 2791 876889 N/A N/A  47322  47341 ACGAATCATGCCACAGTGAA  95 2792 876913 N/A N/A  48676  48695 TACTAGAACACAGTGAAATG 119 2793 876937 N/A N/A  51449  51468 AATACATAGTCTCCCTTGAC  95 2794 876961 N/A N/A  53597  53616 ATTCTTAATCTCCCGTGAAC  74 2795 876985 N/A N/A  56874  56893 CATGGTTCAGGAGGGAAGAG 107 2796 877009 N/A N/A  59869  59888 TCCTTGGAGGATCCAAACTA  99 2797 877033 N/A N/A  62406  62425 TCATAAAGAACTTAAATGTC 135 2798 877057 N/A N/A  64411  64430 ATGGGAAATTATCCCGAAGC 133 2799 877081 N/A N/A  66847  66866 CAAAATACTTCAACACTTCA 119 2800 877105 N/A N/A  68855  68874 AATATAACAAAAATCTGATT 126 2801 877129 N/A N/A  72099  72118 AACCCACACCATTAGGTAGA  90 2802 877153 N/A N/A  73877  73896 TGCAAAAACCAGAGGCACGG  78 2803 877177 N/A N/A  75128  75147 TTTTAAATCAAATTGGATGA 143 2804 877201 N/A N/A  77744  77763 CCCCTCTATAGTATACAAAA  94 2805 877225 N/A N/A  80668  80687 TTAACCTGGAAGCTAAACAG 149 2806 877256 N/A N/A  84735  84754 TGAGAGGTGATGACAGAGCT  99 2807 877280 N/A N/A  87905  87924 TGCACAGAAGAGTTCATTGC  86 2808 877304 N/A N/A  90343  90362 TAAAAAGTTGTCTTCAAAGG  87 2809 877328 N/A N/A  91620  91639 CTTGGTTATTTGTAAAATGT  37 2810 877352 N/A N/A  93973  93992 TTATGTCAAAGCTACAGAGA  60 2811 877376 N/A N/A  95796  95815 TTTTCCAAATTCCTTTGTAT  58 2812 877400 N/A N/A  97827  97846 GAAACAATGAACATCAGTAT  80 2813 877424 N/A N/A 101020 101039 AACTGCTGCAGACTACCAGA  82 2814 877448 N/A N/A 102830 102849 AGCATTTAAATTCAACCTAA 133 2815 877472 N/A N/A 105422 105441 GTAAGGTTGAGAACAAGTGC  80 2816 877496 N/A N/A 108081 108100 AGTAGATTCTGTTATACAAA  53 2817 877520 N/A N/A 110838 110857 AAAAGAGATTATGTCAGATT  86 2818 877544 N/A N/A 112426 112445 GTACTGTCAGAATTAAATTT  76 2819 877568 N/A N/A 115091 115110 GATTTGTTATTTAAAGTAAG 166 2820 877592 N/A N/A 117565 117584 ACAGTGTAAAGTTTTCATCT  58 2821 877616 N/A N/A 119914 119933 GAGTTGCATATGGTTTAGGA  36 2822 877640 N/A N/A 122283 122302 TTCTCATCCAGTGCACACAT  81 2823 877664 N/A N/A 124843 124862 CCTGAAAGTAAGCAGATAAA 141 2824 877688 N/A N/A 127923 127942 AATTCATGCCATTCCAGAAT 143 2825 877712 N/A N/A 132134 132153 ATAAGAAGATTGTTCCTCTC  84 2826 877736 N/A N/A 135027 135046 AGAGAAATAAATGCTCATGG  82 2827 877760 N/A N/A 139725 139744 TATGGAACTTTAAAGAGTTA  93 2828 877784 N/A N/A 141305 141324 ACTTTACTTACTTTTGGTTA  81 2829 877808 N/A N/A 143492 143511 AGACTATGATTAAAACAAAC  88 2830 877832 N/A N/A 145211 145230 ACATCATTGCCCTGTTTGGA  55 2831

TABLE 37 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5’ to 3’) control NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  34  222 876026  711  730  18610  18629 TTTGTTCTCAACAAATTCAG  45 2832 876050  837  856  21668  21687 GCCACTCATGAGGACTTCCA  25 2833 876074 1236 1255  29587  29606 AAGGAGATTATTTAGTGCCC  41 2834 876098 1480 1499  35427  35446 CAGCCACTTCAGGAGAATGT  33 2835 876122 1698 1717  41931  41950 CATATTTAGCTTATGATGAA  66 2836 876146 2449 2468  62070  62089 CACCTTTCCCAATGCTTATC  44 2837 876170 2931 2950  72955  72974 TTCATGATCAAAAATGGGCC  44 2838 876194 3333 3352  76467  76486 ATCTAAAACCACTGAGGGTC  59 2839 876218 3835 3854  82180  82199 ACCATAAATATGCTTTTTCA  36 2840 876242 4311 4330  87215  87234 ACTATAGAATTCCTCACGAC  45 2841 876266 4733 4752  92156  92175 TCAATTGGCACATTTTTACG  71 2842 876290 5067 5086  98215  98234 TTTTTCTAGGAGCTTAAAAT  90 2843 876314 5447 5466 100436 100455 TCCACAACTTGGCCCAAAAG  75 2844 876338 5692 5711 101330 101349 GGTCAGCCAAAATCAAGTCA  76 2845 876362 6427 6446 126543 126562 TCTCAACCATAGGCCATGGG  36   89 876386 7041 7060 137445 137464 ATTTCTTTCCGTTGAATTTG  71 2846 876410 7993 8012 146162 146181 ATCGGCCTTATAAATTTTAG  56 2847 876434 8862 8881 147031 147050 AAGAATTTACCGAAAGTACT  88 2848 876458 N/A N/A   4345   4364 AAATTTCTGGGTTTCCTATG  78 2849 876482 N/A N/A   7014   7033 AGCTCTTTGATCCTCAGTGA  43 2850 876506 N/A N/A   8763   8782 AAAAAGAGAAAGTGCATATA  97 2851 876530 N/A N/A  11858  11877 TGTACAGGAATATGACTAGA  73 2852 876554 N/A N/A  14745  14764 TCCAGCCTCTCTCATGCTAT  94 2853 876578 N/A N/A  16881  16900 TGATAACTGACACAGGGCCC  91 2854 876602 N/A N/A  19380  19399 GGCCCTTCATGCTCTCCACT  81 2855 876626 N/A N/A  21285  21304 AGATAAATAAATTGGAGGGT  76 2856 876650 N/A N/A  24302  24321 ATATTTTTAAGCCCACATTG  83 2857 876674 N/A N/A  27099  27118 TCATCAACGGCCTCACAATC 114 2858 876698 N/A N/A  29500  29519 AATTTTGAATAACTCTAATA 115 2859 876722 N/A N/A  31348  31367 ATGTCATGTGTGAGTTTACA  46 2860 876746 N/A N/A  33423  33442 GGTCTTACTCAATAGTCACC  55 2861 876770 N/A N/A  35317  35336 ACTTATAGATATGAAAGCAT  86 2862 876794 N/A N/A  37818  37837 AAAGATTTACATTTAGTCGA  67 2863 876818 N/A N/A  39048  39067 ATATAACTAGAGAAAATGAT 118 2864 876842 N/A N/A  41389  41408 AAGTTCTGTAAAGGCTATAT  65 2865 876866 N/A N/A  43424  43443 AAAGAAAAGAACCAAGGTTT  67 2866 876890 N/A N/A  47351  47370 GCATTTAGTTTGTTGCCACA  30 2867 876914 N/A N/A  48782  48801 CTAATAAAGTGGATGGATTT 117 2868 876938 N/A N/A  51461  51480 TATCATCTTAATAATACATA  66 2869 876962 N/A N/A  53654  53673 CTCTTGAAGAAAAACTATTT  96 2870 876986 N/A N/A  56900  56919 AGAACAATCAGATAGATATA 105 2871 877010 N/A N/A  59885  59904 TTTGTGGAAGGAATTTTCCT  73 2872 877034 N/A N/A  62466  62485 GTACCCCTTCAAAAAGCTTC  97 2873 877058 N/A N/A  64464  64483 CACTATACCCATATACCCAA  84 2874 877082 N/A N/A  67017  67036 GAAAACTGCATTTCACCAAG  67 2875 877106 N/A N/A  69629  69648 TTATCCAGAAAATCTCCAAA  99 2876 877130 N/A N/A  72373  72392 TCCATAGTTCCAAAACAGAC  76 2877 877154 N/A N/A  73916  73935 CAAAGATGCTCCTGAACATC  87 2878 877178 N/A N/A  75204  75223 CACTGGGAATAGACAGAAAC  68 2879 877202 N/A N/A  77774  77793 GGTTTTGACAAGTGTACCAT  57 2880 877226 N/A N/A  80802  80821 ACCAATAGTGTGTCACTTAA  48 2881 877233 N/A N/A  81930  81949 ACTAGCATTATTGACATATG  98 2882 877257 N/A N/A  84787  84806 TAGTGAGTGAACACAGCCAT  48 2883 877281 N/A N/A  87933  87952 TCCTGACACAAGCTTTTTAA  64 2884 877305 N/A N/A  90378  90397 CTGGTATTTCTCAAAGCATT  40 2885 877329 N/A N/A  91655  91674 TTTTAAATATTCAAGGTAAA  96 2886 877353 N/A N/A  94061  94080 AATGTGCAACAAAGAATTAT  74 2887 877377 N/A N/A  95892  95911 CATTATCTTGACTTTATCAC  78 2888 877401 N/A N/A 98295  98314 TAGCAATTAATTTTTTAAGG  95 2889 877425 N/A N/A 101246 101265 AGAAGTAATAAAACATTTTT 140 2890 877449 N/A N/A 103447 103466 GGGAGAGTAATCACAAACAT  76 2891 877473 N/A N/A 105724 105743 TCTCCTGTTCAGAAACAAAT 103 2892 877497 N/A N/A 108130 108149 GTTTAGAGCAGTAAGTCATG  65 2893 877521 N/A N/A 110906 110925 TAAAATTTGAAATGCATGCT 118 2894 877545 N/A N/A 112696 112715 TACTTAACGAAGATTAAATA 106 2895 877569 N/A N/A 115659 115678 CAAATGCATACTTGCTTTCG  71 2896 877593 N/A N/A 117566 117585 AACAGTGTAAAGTTTTCATC  65 2897 877617 N/A N/A 119915 119934 AGAGTTGCATATGGTTTAGG  39 2898 877641 N/A N/A 122290 122309 TTCTAAATTCTCATCCAGTG  61 2899 877665 N/A N/A 125117 125136 ATGATCATCTGTTTAAGGAA  74 2900 877689 N/A N/A 128242 128261 AGCATAAACAAGAAGGAGAA  80 2901 877713 N/A N/A 132213 132232 AGTTTTGCCTATCAAGATGA  82 2902 877737 N/A N/A 135443 135462 CCTAAGCACCCATGAATGAA  79 2903 877761 N/A N/A 139807 139826 AATCTCTTTTGGGAGATGAG  81 2904 877785 N/A N/A 141341 141360 TAACCATTCTGAATTGAATA  86 2905 877809 N/A N/A 143723 143742 AATTATTATCAAAGGAAGAC 126 2906 877833 N/A N/A 145245 145264 AATTTATGAAACACATAATA 101 2907

TABLE 38 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5’ to 3’) control NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  15  222 803630 N/A N/A  81592  81611 AAAGCCATAGTGTTTGAAGG  66 1792  87849  87868 876015  341  360   3732   3751 ACCTGCTGCACACTCGCGAC  39 2908 876039  824  843 N/A N/A ACTTCCACATTATTGCAAGG  38 2909 876063 1038 1057  28013  28032 CGCTGAGATCTGCAATGCTG  66 2910 876087 1467 1486  35414  35433 AGAATGTATATGCTTCTGCA  75 2911 876111 1499 1518  35446  35465 AGCATTTTACAGCCACTTTC  50 2912 876135 2086 2105  56020  56039 AAGATGCTGACAATTTGAGG  66 2913 876159 2716 2735  65554  65573 ATTTAGACAGCACATCTTCA  76 2914 876183 3222 3241  76356  76375 CAAATGTGTCAAACTCTTCA  42 2915 876207 3752 3771  82097  82116 CAGTGTGCGGGACCTGGTAG  52 2916 876231 3973 3992  83968  83987 ATTTCCCCATTTCATTGGGA  74 2917 876255 4604 4623  88705  88724 CGAAGTTTTGCCAAAGCATC  37 2918 876279 4962 4981  98110  98129 TTTTGGACAACCTTCCACTT  51 2919 876303 5197 5216  99203  99222 AAGGCATTTCATATAGTCGG  31 2920 876327 5646 5665 101284 101303 GAGCCTTGGTTGATCTGGAT  41 2921 876351 6067 6086 N/A N/A TGGCTGAGTGGAGGTATCTC 100 2922 876375 6733 6752 132443 132462 TTTCAACAGGAAGATGCACC  68 2923 876399 7490 7509 143138 143157 AGCTGTGCTGTCATCATGAC  77 2924 876423 8494 8513 146663 146682 AAAAATATCACTTGAAGGAC  76 2925 876447 N/A N/A   3735   3754 TTTACCTGCTGCACACTCGC  44 2926 876471 N/A N/A   5332   5351 TATACATGTATCAAATAGCA  56 2927 876495 N/A N/A   7824   7843 ATCTCTCTAAGAGAGAAGGT 110 2928 876519 N/A N/A  10780  10799 TCTCTTCATGGTTTGAATTC  72 2929 876543 N/A N/A  13667  13686 AAGTTTGCTTATTTGCATTT  75 2930 876567 N/A N/A  15828  15847 TAATTTCATGAGTCTCAATC  89 2931 876591 N/A N/A  17978  17997 CATGTATAAAATTATAGTTT  72 2932 876615 N/A N/A  20147  20166 CAATGTGGGTGGAAAACAAT 107 2933 876639 N/A N/A  23039  23058 ATAGACAATGACCCTTGCTC  38 2934 876663 N/A N/A  26161  26180 TTCTCATGAAAAATAATGAA  80 2935 876687 N/A N/A  28159  28178 TGAGCTACACAGGACAGAAA  90 2936 876711 N/A N/A  30793  30812 CAAAAGCATATGCAGCAGAG  47 2937 876735 N/A N/A  32754  32773 ATCAAAGGAGATTTCCAGGT  33 2938 876759 N/A N/A  34066  34085 AATAAGTAGTCTATCTTAAG 101 2939 876783 N/A N/A  36564  36583 TCCGCTGTGTTTTTGCCTCA  65 2940 876807 N/A N/A  38580  38599 ATGCCTCACTCACCCCCGAC  70 2941 876831 N/A N/A  40880  40899 AAGAAGATGTGACCACTAAA 122 2942 876855 N/A N/A  42917  42936 GTAATTCCCTTCTTCTCTTT  47 2943 876879 N/A N/A  46712  46731 AATACTATTGTTATTTTTAC 126 2944 876903 N/A N/A  48099  48118 CAGGGTGCATAGTCTGTAGG  49 2945 876927 N/A N/A  50346  50365 TCTGAACTTTCTGTTTGATT  35 2946 876951 N/A N/A  52863  52882 GCCCTACAAAAATCTATTCT  53 2947 876975 N/A N/A  56130  56149 GGATGCAAGTGAAAAACACT 103 2948 876999 N/A N/A  57946  57965 CTAGATATAAATAACCTCTG  52 2949 877023 N/A N/A  61194  61213 ATAATATCCATCAGTTACTG  97 2950 877047 N/A N/A  63254  63273 GAAGAGACAGCCAGGTGAAG 126 2951 877071 N/A N/A  66298  66317 ACAATATTTTGGAACAACTC  51 2952 877095 N/A N/A  67597  67616 ATAGGTAATATGATTTAATT 127 2953 877119 N/A N/A  71046  71065 TCATGTTTCATGGTTTCTTT  31 2954 877143 N/A N/A  72871  72890 GGAAGGAACCATGAAATTTT  74 2955 877167 N/A N/A  74441  74460 CCTTGAGAATTTAACAATTT  44 2956 877191 N/A N/A  76594  76613 CTCTTTCTTACCCTTCTAAA 143 2957 877215 N/A N/A  79222  79241 GCAAAGCAAACAGATTTTGA  49 2958 877246 N/A N/A  83653  83672 TCACTCATCTGTAATATTAA  34 2959 877270 N/A N/A  86973  86992 CTAACATATCCCTCCATGTT  69 2960 877294 N/A N/A  89174  89193 CCATAAAACAGGAATTCCAA  84 2961 877318 N/A N/A  91036  91055 ATCTCTTAACCCAGAGAATT  93 2962 877342 N/A N/A  93085  93104 ATATTTGAGACACTGACATG 107 2963 877366 N/A N/A  95216  95235 AATTACTCCACAGAATCTTC 104 2964 877390 N/A N/A  96680  96699 AATTCTAACTCTACCTCTTC 140 2965 877414 N/A N/A  99835  99854 TAAAAAGAAGTTTTTGATCA 100 2966 877438 N/A N/A 102077 102096 ATGTGCAGGAAGTCAAGATA  63 2967 877462 N/A N/A 104952 104971 GTATTATTTGCATCTTATCA  57 2968 877486 N/A N/A 106807 106826 AGTGAGTCTTACAAAAAGTT  73 2969 877510 N/A N/A 110180 110199 GAGAAAAGCACAGATGACTC  46 2970 877534 N/A N/A 111786 111805 CTCTGCAATTCAAAAAAAGT 100 2971 877558 N/A N/A 114104 114123 TAGGCAATGAGAGATGATAC 147 2972 877582 N/A N/A 117147 117166 CAGCTGAAGATTCTCTCTCT  66 2973 877606 N/A N/A 119182 119201 TCAGGATTGGGAACTAAGAA  56 2974 877630 N/A N/A 121116 121135 TTCTCTAAACTTTAGTCTCT  53 2975 877654 N/A N/A 123425 123444 TACTCTTTCAACTGTTCTTT  61 2976 877678 N/A N/A 126753 126772 GGATGGTGAAAATTATAGGA  61 2977 877702 N/A N/A 129321 129340 TTCTATATTGCAGAGCCACC 131 2978 877726 N/A N/A 133413 133432 TTCAGTGGAGTTTAGTTCAG  81 2979 877750 N/A N/A 138222 138241 CCAAGTTCACAAAACCAATA  57 2980 877774 N/A N/A 140803 140822 ATGGCAAACTCCTACTTGGC  97 2981 877798 N/A N/A 142508 142527 TTTTCCCAGAACCAGTGAAT 102 2982 877822 N/A N/A 144769 144788 TTTGGATATGGTAAGGTACA  71 2983

TABLE 39 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5’ to 3’) control NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  18  222 803628 N/A N/A  81589  81608 GCCATAGTGTTTGAAGGAAT  43 1790  87846  87865 876012  338  357   3729   3748 TGCTGCACACTCGCGACTCT  71 2984 876036  802  821  18701  18720 TCGCTAGGGAATGTAAACAA  63 2985 876060  877  896  21708  21727 CTTTCATAGCTTCCACCACA  56 2986 876084 1450 1469  35397  35416 GCATTAACTCCAAAACATTC  32 2987 876108 1491 1510  35438  35457 ACAGCCACTTTCAGCCACTT  63 2988 876132 1957 1976  52997  53016 CATTCTTCTTTGTAATCAAG  53 2989 876156 2621 2640 N/A N/A GCTAGTGTAGATGCTATATT  26 2990 876180 3215 3234 N/A N/A GTCAAACTCTTCAGAGTTTC  21 2991 876204 3660 3679  80940  80959 GGAAAATTTGTTCTGAGATA  20 2992 876228 3924 3943  83919  83938 ATCCAGAGATGTCAGATTTT 131 2993 876252 4427 4446 N/A N/A GCGCGAGCCTTTATATTGAA  95 2994 876276 4816 4835  92239  92258 CGTGAGGAAGCTCATTTTCA  30  148 876300 5193 5212  99199  99218 CATTTCATATAGTCGGATGA  46 2995 876324 5571 5590 100560 100579 TTGATGTTCTTCACCATCAT  57 2996 876348 5984 6003 113181 113200 TGCTGAAGCAGGCGATCCAA  97 2997 876372 6650 6669 129795 129814 TCAAGAAATGAGAGCTGTCC  87 2998 876396 7395 7414 143043 143062 TCCTCCAGTTCCTATCCAAA  87 2999 876420 8397 8416 146566 146585 ATGTCTAGGAAAGACACAGA 119 3000 876444 9175 9194 147344 147363 ATTTAAATATGGTATTCATT 145 3001 876468 N/A N/A   5184   5203 ACTCATAACTACTCCGGACA 101 3002 876492 N/A N/A   7482   7501 TGGCAGTCTGGAATATCATG  62 3003 876516 N/A N/A  10656  10675 AATCAAACTTCTGAGTTTAA  78 3004 876540 N/A N/A  13053  13072 AGCACTACTTATTTTCCAAT  34 3005 876564 N/A N/A  15510  15529 AGGCACCTTCATTCCTATTG  63 3006 876588 N/A N/A  17889  17908 TTTTAATTTTATGCCAGAGT  42 3007 876612 N/A N/A  19937  19956 TTGTGATTTTATAAACATCA  72 3008 876636 N/A N/A  22628  22647 TTAACCCTTATTTATATATG 104 3009 876660 N/A N/A  25657  25676 TTATATACATCTGTGTATAA  85 3010  25687  25706  25717  25736  25747  25766  25811  25830  25875  25894 876684 N/A N/A  27860  27879 TTAACATATAACACTATTTA 119 3011 876708 N/A N/A  30296  30315 CAGAGGATACCCATTGCAAA  60 3012 876732 N/A N/A  32607  32626 CCTCTTTAACTGCACAGTAG  38 3013 876756 N/A N/A  33886  33905 AACCTTTCCCAAAGTGGCTA  56 3014 876780 N/A N/A  36392  36411 TAACCCTACTTCTTACAAGT 109 3015 876804 N/A N/A  38436  38455 CATCGATATTCTCAAAGCCT  45 3016 876828 N/A N/A  40375  40394 TACTTAAAATACTTCAAACA 110 3017 876852 N/A N/A  42387  42406 ACCATATACTATGAGACCAG  40 3018 876876 N/A N/A  45845  45864 GGAATTACAGTGGAGAGGTT 107 3019 876900 N/A N/A  48095  48114 GTGCATAGTCTGTAGGTAGT  28 3020 876924 N/A N/A  50233  50252 GCTCTGTTGTCACCCTTGTA  62 3021 876948 N/A N/A  52394  52413 CATTAGAAGATGAATTCACT 104 3022 876972 N/A N/A  55581  55600 ATAATATTGAACAGTAGGTT  84 3023 876996 N/A N/A  57799  57818 CTGTTGGGTAGAAAGATTTG  85 3024 877020 N/A N/A  60838  60857 GGTTGGAAGGCACCAATTAA  76 3025 877044 N/A N/A  63123  63142 AGCCTACTGAGCGGTTGGAA  82 3026 877068 N/A N/A  66018  66037 GTTGCAGACATTTTACATAC  32 3027 877092 N/A N/A  67322  67341 TAGAACCATACCTAAATAGT  97 3028 877116 N/A N/A  70348  70367 GTAATACCCGAAAGAAGGGA  53 3029 877140 N/A N/A  72680  72699 TGAAAAAGCTATATCCATAT 120 3030 877164 N/A N/A  74213  74232 AAAAAAAACTTTCAGTAATC 142 3031 877188 N/A N/A  76212  76231 AACACAATCCACAACAGAAT  89 3032 877212 N/A N/A  78681  78700 AGGAGGAAAATACTATCCAA  59 3033 877243 N/A N/A  83326  83345 TATATGCACAGTTTTGCTGA  71 3034 877267 N/A N/A  86866  86885 AGAACAGAAAGCTCAGTTTT  80 3035 877291 N/A N/A  89005  89024 CTCTCAGAAACATTTTCTCA  66 3036 877315 N/A N/A  90693  90712 AACAAAACTTAAAAGTGTCT 166 3037 877339 N/A N/A  92828  92847 AAACAACTCACACATTTCTA  84 3038 877363 N/A N/A  95003  95022 AGTTGAGTTACCTCCTGATA  72 3039 877387 N/A N/A  96290  96309 TCTGGTTACTAGAATGTAGC 104 3040 877411 N/A N/A  99458  99477 GATTGCCTACTCCAAGGTTT  56 3041 877435 N/A N/A 101844 101863 AGGCTTTTAATGAATATTTC  80 3042 877459 N/A N/A 104859 104878 GGTATTGAGAGAGCTTCAGA  51 3043 877483 N/A N/A 106692 106711 GAAAAGACAAACTAGGATTG  70 3044 877507 N/A N/A 109824 109843 GTAGAACAGAGTCTGAAGTA  67 3045 877531 N/A N/A 111551 111570 CTGTAACTCTGTTGAAATGT  96 3046 877555 N/A N/A 113739 113758 TCAAAGACCACAGCCTTTCC 116 3047 877579 N/A N/A 116515 116534 GCTAAGAGACTTCTTTCTTC  48 3048 877603 N/A N/A 118863 118882 ACTAAAGTTTTTGCTGTTAC  51 3049 877627 N/A N/A 120815 120834 CGGAAAAGACAAGAAGATAA  82 3050 877651 N/A N/A 122955 122974 TTATCATGTGAATTAGCATA  47 3051 877675 N/A N/A 126419 126438 CCAGACATTGCAAAGAAAAA  65 3052 877699 N/A N/A 129171 129190 AGTGTGAAGGCACCGTAAGA  73 3053 877723 N/A N/A 133344 133363 CCAATTCCATCCATTGAAAT  69 3054 877747 N/A N/A 137747 137766 AAAAGTGATTAGGTTGAGTG  62 3055 877771 N/A N/A 140595 140614 TATTTTCTACATACCCCTCG  93 3056 877795 N/A N/A 142281 142300 ATCTAAAATGTTCTCAAGAG 136 3057 877819 N/A N/A 144428 144447 GTTGGCTTCTCAGAGGTTTT  50 3058

TABLE 40 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5’ to 3’) control NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  24  222 803632 N/A N/A  81595  81614 TAAAAAGCCATAGTGTTTGA  91 1794  87852  87871 876018  441  460  10465  10484 ACCAAGGACTTCCCAATCAT  69   32 876042  828  847  21659  21678 GAGGACTTCCACATTATTGC  19 3059 876066 1105 1124  29366  29385 TCTCATTCTTTTCCTCTAAA  30 3060 876090 1471 1490  35418  35437 CAGGAGAATGTATATGCTTC  25 3061 876114 1580 1599  37629  37648 CGTTTCATAACTGTTAGTAT  46 3062 876138 2218 2237  56226  56245 CATCCATAGCTACTTTTGCA  54 3063 876162 2848 2867  71691  71710 ATTCTCCTACACTAATTGAA  64 3064 876186 3225 3244  76359  76378 GTCCAAATGTGTCAAACTCT  20 3065 876210 3797 3816  82142  82161 ATCTGATTATGGCTAAATAA  48 3066 876234 4048 4067  84043  84062 TGGCTTTACATCCTATATGT  43 3067 876258 4692 4711  92115  92134 AAGTTCTACATAGCAGTCTG  34 3068 876282 5044 5063  98192  98211 GTGACATGTAGTTCTTTGGA  11 3069 876306 5201 5220  99207  99226 AAATAAGGCATTTCATATAG  56 3070 876330 5650 5669 101288 101307 TGGTGAGCCTTGGTTGATCT  42 3071 876354 6155 6174 118488 118507 TAGTCAGCAATCTTTGCAAT  96 3072 876378 6782 6801 132492 132511 ATGACCAGGAGAGTACCAGA  69 3073 876402 7537 7556 145140 145159 TTTTCCGGTTGTAGCCCAAT  70 3074 876426 8594 8613 146763 146782 TGTAGGATCTGCAGCATCAC  60 3075 876450 N/A N/A   3743   3762 ACAATGCCTTTACCTGCTGC  98 3076 876474 N/A N/A   5889   5908 TACTTCAGCCCAGGATTGCA  70 3077 876498 N/A N/A   7911   7930 CTACATGGAACTTCTGTGAT  71 3078 876522 N/A N/A  10992  11011 CAGATGTGCTGAAAGTTAAT  62 3079 876546 N/A N/A  14076  14095 ATGAGATTTTTGAGAGGCAA 107 3080 876570 N/A N/A  15984  16003 AATTTTTACATGAAGACTGT  83 3081 876594 N/A N/A  18271  18290 CTAGAGAAAACTGACAGTGA  80 3082 876618 N/A N/A  20538  20557 AAAGACTCTACCAGAAAAAG 106 3083 876642 N/A N/A  23590  23609 AATGTATGGTGACTTGACCT  97 3084 876666 N/A N/A  26378  26397 AACAAAACCACTTCTTCTTC  69 3085 876690 N/A N/A  28864  28883 TGAAGAGAAAACCACACACT  50 3086 876714 N/A N/A  30858  30877 TTATAGTTCATTTTTTAAGA 159 3087 876738 N/A N/A  32945  32964 ACTCCAAAGACAATACAAAA 102 3088 876762 N/A N/A  34263  34282 CAACTGGCCAATTTTCCTCT  60 3089 876786 N/A N/A  36893  36912 GATACATTCCTTCTTTTCCA  50 3090 876810 N/A N/A  38645  38664 CCTTTTCTTTGGGCCTCAGC  55 3091 876834 N/A N/A  40906  40925 ACTTCTGAGGCTGCCTATTA 102 3092 876858 N/A N/A  42989  43008 CCAATTCATCTTATGCAAAA  50 3093 876882 N/A N/A  46918  46937 ATTTCCTGAGCCACCCTTCT  62 3094 876906 N/A N/A  48113  48132 ATTAAGTACTTGTCCAGGGT  41 3095 876930 N/A N/A  50500  50519 GACACAGAGAGCTGTGAGCA  73 3096 876954 N/A N/A  53300  53319 GAATAACCATGCTGACTTTA  66 3097 876978 N/A N/A  56491  56510 AAGACACAAACAATTGCAAT  98 3098 877002 N/A N/A  59243  59262 TGATAGAAGTGTTTGGTTTT  60 3099 877026 N/A N/A  61360  61379 GGTTAGCATGTGAGGTGCCA  83 3100 877050 N/A N/A  63441  63460 AAGGTTACAACCATGAACAA 158 3101 877074 N/A N/A  66455  66474 ATATTGCATAACTTAATAGC 106 3102 877098 N/A N/A  68250  68269 AGAGCATTTTTCAACACCTA  13 3103 877122 N/A N/A  71326  71345 ATAGTCCAGCAGGAAAAAGC  81 3104 877146 N/A N/A  73085  73104 TGAATAATTGGAGGAAATTC  98 3105 877170 N/A N/A  74875  74894 CTCTGTCTCCAGATATAAAA  27 3106 877194 N/A N/A  77081  77100 AATTAGTTGTAAAAATGTAA 118 3107 877218 N/A N/A  79715  79734 CAGGACACTCCTAGAAGCTG  44 3108 877249 N/A N/A  84418  84437 TGCTATATGAAATACAGTGT  58 3109 877273 N/A N/A  87070  87089 GACCATGTTTAGAGAACTAT  48 3110 877297 N/A N/A  89927  89946 TTACATGACATTACCATCTA  50 3111 877321 N/A N/A  91204  91223 CAGAATTTCTGCTTAAATTC  56 3112 877345 N/A N/A  93276  93295 GAAACATGGAATCTAGAACA 150 3113 877369 N/A N/A  95294  95313 CAAATTAACTTAATTTTTAC 125 3114 877393 N/A N/A  97092  97111 GCCCAAGGACTTGTCTTACC  52 3115 877417 N/A N/A 100614 100633 GTATCAAAACATACCTTCCT 108 3116 877441 N/A N/A 102459 102478 TTCTCACCACATAAATATTT  67 3117 877465 N/A N/A 105189 105208 CCTTGAAATGTAGTCACTTG  61 3118 877489 N/A N/A 107021 107040 ACAGAAGGCGAAGTCAGGAG  90 3119 877513 N/A N/A 110256 110275 GGCCACAGTGATCAGTTTGG  56 3120 877537 N/A N/A 112156 112175 AAAAAATACATATCATCCCC 124 3121 877561 N/A N/A 114361 114380 ATAATCCTTTATAATAAGTA 118 3122 877585 N/A N/A 117351 117370 CACAAGACTTAATGGAGTTA  61 3123 877609 N/A N/A 119274 119293 AACAAATGCCAACCCCTAAA 103 3124 877633 N/A N/A 121503 121522 TATAGTATTTATATGGGTGT  50 3125 877657 N/A N/A 124119 124138 ACAAAGGGAAATGGTTAAAC  40 3126 877681 N/A N/A 126991 127010 ACGGGCACCCTACAAGAAAT 117 3127 877705 N/A N/A 129885 129904 AGTAACTTTCCAAATGGTAT  69 3128 877729 N/A N/A 134033 134052 CTCTGCCCCTTTTCCCAGAC  83 3129 877753 N/A N/A 138357 138376 TTACCAGGTGCTGGTCATTA  24 3130 877777 N/A N/A 140907 140926 ATAAAGAAAAATTACGAACA  79 3131 877801 N/A N/A 142946 142965 TTTACCATTACCTCCCTAGA  61 3132 877825 N/A N/A 144861 144880 CAGCTTAACCTTTCTATAAA  60 3133

TABLE 41 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5’ to 3’) control NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  16  222 876020  528  547  13794  13813 GAGGAGATCTAAGGTCTTCA  35 2603 876044  830  849  21661  21680 ATGAGGACTTCCACATTATT  47 2604 876068 1161 1180  29422  29441 ACAGGCTTCCAGCCAAAACA  63 2605 876092 1473 1492  35420  35439 TTCAGGAGAATGTATATGCT  46 2606 876116 1637 1656  37686  37705 ATAAAATGTAAAATAGCTCG 112 2607 876140 2262 2281  56270  56289 ATTCTGATCACACGCTCTCT  42 2608 876164 2869 2888  71712  71731 GTAATACGGCATCTCGGTAA  66 2609 876188 3228 3247  76362  76381 CAAGTCCAAATGTGTCAAAC  58 2610 876212 3800 3819  82145  82164 CTGATCTGATTATGGCTAAA  59 2611 876236 4144 4163  86639  86658 TTTTACCACTCCCAGTATTT 114 2612 876260 4725 4744  92148  92167 CACATTTTTACGCTCCGATA  31 2613 876284 5046 5065  98194  98213 CTGTGACATGTAGTTCTTTG  39 2614 876308 5338 5357 100190 100209 CTTCAGGAGACCAATTTAAG  48 2615 876332 5652 5671 101290 101309 AATGGTGAGCCTTGGTTGAT  57 2616 876356 6204 6223 118537 118556 GCCCTCTGATGTTTTTATCC  98 2617 876380 6826 6845 132536 132555 TCATCTTTTCTAGGGTATGT  43 2618 876404 7660 7679 145829 145848 TTTCAGCTAATTCTTTTCTC  56 2619 876428 8683 8702 146852 146871 GAAAAGTGTTAGATATTTAT 135 2620 876452 N/A N/A   3761   3780 GAATGAGTTGAAGTGAAAAC 120 2621 876476 N/A N/A   6208   6227 ATCCAGTAATCTCATCGCTG  47 2622 876500 N/A N/A   8095   8114 ATTCTGAACAGCTTCTGGTG 136 2623 876524 N/A N/A  11128  11147 TTTTCCTGGAAACACATTCT 114 2624 876548 N/A N/A  14203  14222 AAGGGCAGGAATGACCACTA  72 2625 876572 N/A N/A  16432  16451 GCAATTGAAGAAAGTCTACT  56 2626 876596 N/A N/A  18903  18922 GTTTCTCCAGCACCAAGCCC  49 2627 876620 N/A N/A  20690  20709 TTCCAGAAGGGCAACCAATG 100 2628 876644 N/A N/A  23667  23686 GAACTGGACAAGTTAATCCT  47 2629 876668 N/A N/A  26426  26445 TGCTGTTCTAGACAATTTGG  46 2630 876692 N/A N/A  29204  29223 AAGCCTTGGTCAATTATAAA  91 2631 876716 N/A N/A  30940  30959 CACTTGCCATTATCAAATAT  84 2632 876740 N/A N/A  33139  33158 TGTATGCAACCTTGGGACCT  57 2633 876764 N/A N/A  34714  34733 TGGAAAGCATTTACATAGAA  47 2634 876788 N/A N/A  36957  36976 TGTTAACTGAAACTTGTGCA  70 2635 876812 N/A N/A  38785  38804 TCTATCATCCTCTGCACCAC  69 2636 876836 N/A N/A  41061  41080 TAAGGAAGGCAGCCTTGATA  54 2637 876860 N/A N/A  43045  43064 TTTATAAAAATGTTCACACT 112 2638 876884 N/A N/A  47090  47109 AATCTCATCCATCTGTAATT  50 2639 876908 N/A N/A  48315  48334 TACTCTGATTTCCTCATCTT  58 2640 876932 N/A N/A  50766  50785 CTTTACAATGTCTTCTTTTA 139 2641 876956 N/A N/A  53309  53328 ATAAATGGTGAATAACCATG  60 2642 876980 N/A N/A  56543  56562 TGGATAACACCTAAAGGACC 122 2643 877004 N/A N/A  59276  59295 GTATTTGGAGCAGTGCCCAG 110 2644 877028 N/A N/A  61596  61615 GTACCTTAACACAGTAAATA  82 2645 877052 N/A N/A  63476  63495 TAATCTACTATGTGCAAAAC 100 2646 877076 N/A N/A  66557  66576 TCTACATTGTCAGGAAGCAA  66 2647 877100 N/A N/A  68445  68464 ATCTCTCACAGATGCAAAAT  82 2648 877124 N/A N/A  71781  71800 ATAATCACAATTGCACAATT 109 2649 877148 N/A N/A  73144  73163 GAATCATTAGGTAAATATAT  99 2650 877172 N/A N/A  74948  74967 AGTGGAGAAGAGAGAAAGAC  92 2651 877196 N/A N/A  77137  77156 TATCAAAAACAATTTGCTTT 136 2652 877220 N/A N/A  79895  79914 ACAGTCTCTTTTCTTATCTG  76 2653 877232 N/A N/A  81609  81628 TTTAGTGTCAATTCTAAAAA 119 2654 877251 N/A N/A  84464  84483 CAGTAGCTATAATGCTTTAA  80 2655 877275 N/A N/A  87627  87646 TTTAGATTTCATTTAAGAAA 105 2656 877299 N/A N/A  89982  90001 AATTACATGTCCAACAAGAG  92 2657 877323 N/A N/A  91362  91381 AATAAAAGTATCTTCCAAAC  91 2658 877347 N/A N/A  93509  93528 AAATTCACAAAAGTTTCTGC  80 2659 877371 N/A N/A  95698  95717 TTTCATATCTCTTTTATCAT  97 2660 877395 N/A N/A  97239  97258 TTTTGCTTTGTCAAATTCAC  45 2661 877419 N/A N/A 100725 100744 CTATAATTGAATATACTATT 108 2662 877443 N/A N/A 102592 102611 ATTAAATCAATCTAATGCAT 105 2663 877467 N/A N/A 105313 105332 CTCAATCCCCAAGGAGTTTG  60 2664 877491 N/A N/A 107115 107134 CTTTCACCCTGAACACACAG  68 2665 877515 N/A N/A 110361 110380 CTCAACCCTCACCCATGCAG  93 2666 877539 N/A N/A 112217 112236 CCTGCTTATAATCTCTGGTT  87 2667 877563 N/A N/A 114595 114614 TCTGAAGGCTTACTATTTTA  71 2668 877587 N/A N/A 117410 117429 ACTACAGCATTTCATGTGAT  46 2669 877611 N/A N/A 119355 119374 ATGTATAGCCACCTGTAATT  93 2670 877635 N/A N/A 121814 121833 CTTGGATAATTATCATAATG  41 2671 877659 N/A N/A 124271 124290 TCTCTTGGGTTCATGCCTGA  67 2672 877683 N/A N/A 127120 127139 TAAATATTTTTGTAGCTCTA  83 2673 877707 N/A N/A 130019 130038 TGTTTCTAGGGACCCTGAGC  58 2674 877731 N/A N/A 134194 134213 AAATGTTGAAATTGTTACAA 150 2675 877755 N/A N/A 138536 138555 AAATGACAATTAGGAGGGTC  78 2676 877779 N/A N/A 141131 141150 CTTGCAAAACTTTGTTTCAT  66 2677 877803 N/A N/A 143288 143307 AATTTATACCAGTCTTATGT 126 2678 877827 N/A N/A 144888 144907 ATTCTTAATTATGTGAGTCT  77 2679

TABLE 42 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5’ to 3’) control NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  35  222 803640 N/A N/A  81631  81650 TGCAGCATCATGCAAGCAGC  22 1802  87888  87907 876022  547  566 N/A N/A TGATTTTACCTGAAGTTAGG  82 3134 876046  832  851  21663  21682 TCATGAGGACTTCCACATTA  50 3135 876070 1231 1250  29582  29601 GATTATTTAGTGCCCAGCAT  47 3136 876094 1475 1494  35422  35441 ACTTCAGGAGAATGTATATG  58 3137 876118 1683 1702  41916  41935 ATGAAATTCTGTATCCTCCC  70 3138 876142 2306 2325  56314  56333 GCATCTGCTCCCAATAGAAG  48 3139 876166 2871 2890  71714  71733 CTGTAATACGGCATCTCGGT  25 3140 876190 3231 3250  76365  76384 GTGCAAGTCCAAATGTGTCA  15 3141 876214 3803 3822  82148  82167 ATGCTGATCTGATTATGGCT  76 3142 876238 4190 4209  86685  86704 CCAAGATCTGATTTCTTGGT  72  139 876262 4728 4747  92151  92170 TGGCACATTTTTACGCTCCG  26 3143 876286 5049 5068  98197  98216 ATACTGTGACATGTAGTTCT  24 3144 876310 5429 5448 N/A N/A AGAATACAGCCTTTTCTACA  53 3145 876334 5655 5674 101293 101312 TGGAATGGTGAGCCTTGGTT  41 3146 876358 6249 6268 124880 124899 AATGACATTTCCTCTGGCAA  69 3147 876382 6870 6889 132580 132599 TTGCTTGGAAAAGGAATTGC  63 3148 876406 7747 7766 145916 145935 AATAAATATTTACAAGAGGA 165 3149 876430 8774 8793 146943 146962 GCTATGTAAACAATTTAAGT  96 3150 876454 N/A N/A   4075   4094 ATTGGGAAGATACTTGGAAT  86 3151 876478 N/A N/A   6864   6883 ACACAAATCATTTCAAAATG  80 3152 876502 N/A N/A   8430   8449 GGCACAAGTTTCTTACTCGC  56 3153 876526 N/A N/A  11515  11534 TCTAATTTGTCTAAATTTAT 120 3154 876550 N/A N/A  14441  14460 CTCTGCACTTCAGTGTTTGT  55 3155 876574 N/A N/A  16653  16672 ATCTCAGTTATCAATCTCAG  51 3156 876598 N/A N/A  19231  19250 ATAACCCCACACCTTTACTG 239 3157 876622 N/A N/A  20813  20832 CGAGGCTCAACCCCATTGGA  58 3158 876646 N/A N/A  23976  23995 TATATAATTGCTAGGTAGAG  52 3159 876670 N/A N/A  26660  26679 TCATTCAGCTACTTTTGAAA  55 3160 876694 N/A N/A  29232  29251 ACCAACAGAATGAGGTGTGC  36 3161 876718 N/A N/A  30990  31009 ATTCAAACAAAATGTTAGTA 125 3162 876742 N/A N/A  33417  33436 ACTCAATAGTCACCTTCTTT  60 3163 876766 N/A N/A  34874  34893 ATGTGGAGGTATCGACCATT  32 3164 876790 N/A N/A  37365  37384 CGGGAATTATTTCACTTCAT  21 3165 876814 N/A N/A  38809  38828 CCTTGTATCTAGTCTCTCTC  49 3166 876838 N/A N/A  41299  41318 CTACAAGTCAAAAATGTGGT  71 3167 876862 N/A N/A  43081  43100 ATCATTTCCATTAATTATTT  72 3168 876886 N/A N/A  47247  47266 CTTAGAATGAAATTGCTGAT  48 3169 876910 N/A N/A  48381  48400 TGCCAATGTGGAGTTAATTT 103 3170 876934 N/A N/A  50807  50826 TAATTATTCTCAGTCTTTAA 110 3171 876958 N/A N/A  53342  53361 TCTTAGCACATTCTCTGAAC  61 3172 876982 N/A N/A  56609  56628 GACACATTTGAAAAGTTATT  45 3173 877006 N/A N/A  59726  59745 TCTTTAGAATATTCACACAT 112 3174 877030 N/A N/A  61906  61925 ACTGGCAAATCAAACTTCAT 104 3175 877054 N/A N/A  63890  63909 AATGTAATCTTTATCAGGAC  65 3176 877078 N/A N/A  66625  66644 TTGGAAAACAGACACAAAAG  61 3177 877102 N/A N/A  68600  68619 GGCCTTTGCTGGTGAAGTCT  39 3178 877126 N/A N/A  71855  71874 GAAATCCCTACCAATTGTTC 119 3179 877150 N/A N/A  73433  73452 CAATCAGGCTTTCTTCAAGG  88 3180 877174 N/A N/A  75007  75026 TGATGAAGTGACAGTTAAAT 116 3181 877198 N/A N/A  77396  77415 GTACAACTTAGAGGGCCTGG  38 3182 877222 N/A N/A  80337  80356 AGTTCTCAATACTCTGGTAT  35 3183 877253 N/A N/A  84478  84497 ATTTCACATGATGTCAGTAG  61 3184 877277 N/A N/A  87800  87819 AGATAGAAAAGCAACAAAAG 153 3185 877301 N/A N/A  90174  90193 CAACAAGTCTTTTTAAAGAT  74 3186 877325 N/A N/A  91493  91512 AACATCAGTGATTCTGATAG 136 3187 877349 N/A N/A  93656  93675 GGATCTAGTAAAGCAGCATG  39 3188 877373 N/A N/A  95702  95721 TCTCTTTCATATCTCTTTTA  42 3189 877397 N/A N/A  97648  97667 GAATAGGAAGACAGACTGTG  69 3190 877421 N/A N/A 100889 100908 TCTTTATAACAGTTCTATGA  99 3191 877445 N/A N/A 102737 102756 GACAACTTTTTGCTAATAAT  70 3192 877469 N/A N/A 105355 105374 TTCAGGCCTCCATACCCTTG 184 3193 877493 N/A N/A 107755 107774 AGAGAATCCATTTGACTTTG  37 3194 877517 N/A N/A 110432 110451 GAATACAGGAATAACCACTG  61 3195 877541 N/A N/A 112355 112374 AACAGTGCACACAGTGTAGT  46 3196 877565 N/A N/A 114614 114633 CTACTGTCAACACAGTAATT  72 3197 877589 N/A N/A 117436 117455 CTTCTCTGCCCCATGATGTC  56 3198 877613 N/A N/A 119406 119425 TTTCTTCTGTGCCAGGCACG  47 3199 877637 N/A N/A 121914 121933 GCCACTATTAAGTGGTAGAG  52 3200 877661 N/A N/A 124653 124672 CCAAGGTTGACCACACAGGA  66 3201 877685 N/A N/A 127508 127527 TCATAAGATTTGACAGCATG  48 3202 877709 N/A N/A 130133 130152 TTCAGAAACCACATTTCTGC 123 3203 877733 N/A N/A 134456 134475 CAATCAGCAAGTATTTTCAG 113 3204 877757 N/A N/A 138991 139010 GTGGTGCTTGGACTGAAATA  85 3205 877781 N/A N/A 141186 141205 TTGTACTATATCTAAATTTC  89 3206 877805 N/A N/A 143353 143372 TAATCTGCTTCTCTTGTGGG  71 3207 877829 N/A N/A 145054 145073 ATATTAAACTGGCCTGAAAA 145 3208

TABLE 43 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5’ to 3’) control NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  49  222 803641 N/A N/A  81632  81651 TTGCAGCATCATGCAAGCAG  57 1803  87889  87908 876023  662  681  16182  16201 AGCACATGTAAAGCTTTGCA  51 3209 876047  833  852  21664  21683 CTCATGAGGACTTCCACATT  60 3210 876071 1232 1251  29583  29602 AGATTATTTAGTGCCCAGCA  43 3211 876095 1476 1495  35423  35442 CACTTCAGGAGAATGTATAT  35 3212 876119 1694 1713  41927  41946 TTTAGCTTATGATGAAATTC  36 3213 876143 2395 2414  62016  62035 CACTATTCAGTAAGAGTTCC  19 3214 876167 2873 2892  71716  71735 CGCTGTAATACGGCATCTCG  58 3215 876191 3250 3269  76384  76403 ATGATGTAAATTTATTACTG  75 3216 876215 3804 3823  82149  82168 GATGCTGATCTGATTATGGC  33 3217 876239 4232 4251  86727  86746 GGCCAGTCTTTCACATCTAT  39 3218 876263 4729 4748  92152  92171 TTGGCACATTTTTACGCTCC  21 3219 876287 5050 5069  98198  98217 AATACTGTGACATGTAGTTC  38 3220 876311 5434 5453 N/A N/A CCAAAAGAATACAGCCTTTT  52 3221 876335 5660 5679 101298 101317 GATATTGGAATGGTGAGCCT  28 3222 876359 6288 6307 124919 124938 TAGTAAACCAAATGAATAAA  78 3223 876383 6953 6972 N/A N/A CCTTTAAGCTTAACAGTCTT 125 3224 876407 7856 7875 146025 146044 TTACTGGTAAGTATTTTTAC  57 3225 876431 8779 8798 146948 146967 GGTAAGCTATGTAAACAATT 105 3226 876455 N/A N/A   4112   4131 AACTATTCATAATCTTCTCA  93 3227 876479 N/A N/A   6910   6929 TTGGCTGTGCAAAAGAAGGA 112 3228 876503 N/A N/A   8563   8582 CTGCTACATGATAAGGAAGC  62 3229 876527 N/A N/A  11614  11633 CACACCCTTTATGTACTGAA  33 3230 876551 N/A N/A  14462  14481 TCTTAGTGGCCAAAGCAACT  80 3231 876575 N/A N/A  16768  16787 TCACAAGCTCTGTGTCCTCA  45 3232 876599 N/A N/A  19233  19252 TCATAACCCCACACCTTTAC  91 3233 876623 N/A N/A  20902  20921 TTTTTTTTGATGTGGAGAAA 161 3234 876647 N/A N/A  24058  24077 GACTCATGTAAGAAGACAAG  48 3235 876671 N/A N/A  26694  26713 TTTAATTTTAACTATGAAGA 101 3236 876695 N/A N/A  29272  29291 TAACAGTTTGACCAACTCTA  76 3237 876719 N/A N/A  30991  31010 AATTCAAACAAAATGTTAGT 180 3238 876743 N/A N/A  33419  33438 TTACTCAATAGTCACCTTCT  62 3239 876767 N/A N/A  34973  34992 TTCCAATACTTAAAACAAGT  76 3240 876791 N/A N/A  37386  37405 AAGATAGAATTCATAGTAAT 108 3241 876815 N/A N/A  38831  38850 CCATGGACCTCCAACCCAAT  86 3242 876839 N/A N/A  41301  41320 CACTACAAGTCAAAAATGTG  62 3243 876863 N/A N/A  43157  43176 ATTTTTAAGGGAGATCTCTC  56 3244 876887 N/A N/A  47300  47319 TTCATGTCTAATAATCTTTA  64 3245 876911 N/A N/A  48530  48549 TCTAAAGAAATTCAGACAAC 115 3246 876935 N/A N/A  50878  50897 CAAAGAAAAAAGTCCAATAA 168 3247 876959 N/A N/A  53439  53458 GCAACCTGCAATAAAACCCA  43 3248 876983 N/A N/A  56638  56657 AGACTAAGTTGTAGAGATGC  79 3249 877007 N/A N/A  59787  59806 TAAAATAAATAAATGCCAGC 125 3250 877031 N/A N/A  62296  62315 ACTAAAAGACTAGTGACTTA  69 3251 877055 N/A N/A  64013  64032 GAACCCATTTCTGGAGGGTT 180 3252 877079 N/A N/A  66732  66751 CACTAGAACAGCTAAAAGTA 172 3253 877103 N/A N/A  68807  68826 TCACTAACAGGATAATTAAA 103 3254 877127 N/A N/A  72021  72040 TGAAGTGTACTGTAAGTATA  46 3255 877151 N/A N/A  73765  73784 CTTGAAAGTTACAAGGATAA  60 3256 877175 N/A N/A  75058  75077 GGTGGGTAGGTTGGCTGGAG  88 3257 877199 N/A N/A  77450  77469 ACTGAAATGCCACTTTTAAA  74 3258 877223 N/A N/A  80422  80441 ATGGGTGTTATTTAATAAAA  65 3259 877254 N/A N/A  84582  84601 AAGTGTAAAGACCAGAAACA 169 3260 877278 N/A N/A  87864  87883 TAGTCTCCATTCTAAAAAGC  64 3261 877302 N/A N/A  90291  90310 GACTTATTGGTAATGATATC  57 3262 877326 N/A N/A  91566  91585 GCAGAGACATAAAATCCCAC  36 3263 877350 N/A N/A  93891  93910 TTCCATGTGAAATATAAGAA  79 3264 877374 N/A N/A  95756  95775 AAGGTTAAATTGCCATGTAA  45 3265 877398 N/A N/A  97666  97685 CTAGGAGAGGACTTCCATGA  52 3266 877422 N/A N/A 100940 100959 ATTATATGGCAGACATGTTG  73 3267 877446 N/A N/A 102740 102759 TTGGACAACTTTTTGCTAAT  72 3268 877470 N/A N/A 105358 105377 ACCTTCAGGCCTCCATACCC  95 3269 877494 N/A N/A 107793 107812 CCTTTATTTTTATAAATTGA  51 3270 877518 N/A N/A 110571 110590 TACAGTTGAGTTCTGGTATA 100 3271 877542 N/A N/A 112357 112376 GAAACAGTGCACACAGTGTA  56 3272 877566 N/A N/A 114956 114975 AAAAACTAGAACCTAGAGTT  90 3273 877590 N/A N/A 117469 117488 AGATGTCTATAAAATTCTGA  77 3274 877614 N/A N/A 119511 119530 AACCAGGCATTGGAATCTGG  65 3275 877638 N/A N/A 121934 121953 AATTTCTTGATGAACATCAT  69 3276 877662 N/A N/A 124733 124752 CTAAACCAGGCTGTGTTATT  75 3277 877686 N/A N/A 127511 127530 TTTTCATAAGATTTGACAGC  83 3278 877710 N/A N/A 130554 130573 TTTAACCTCAGAACTAATGT  152 3279 877734 N/A N/A 134509 134528 ATCAGATGTCATTTATCATT  67 3280 877758 N/A N/A 139025 139044 AGCACAAAGTCACCTAACCT  50 3281 877782 N/A N/A 141209 141228 TCTATGTGGCTCTTTGTAGA  50 3282 877806 N/A N/A 143361 143380 AGCTGCAGTAATCTGCTTCT  33 3283 877830 N/A N/A 145056 145075 ATATATTAAACTGGCCTGAA 152 3284

TABLE 44 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5’ to 3’) control NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  23  222 780625 N/A N/A  81633  81652 ATTGCAGCATCATGCAAGCA  56  675  87890  87909 876024  667  686  16187  16206 CAAACAGCACATGTAAAGCT  75 3285 876048  834  853  21665  21684 ACTCATGAGGACTTCCACAT  42 3286 876072 1233 1252  29584  29603 GAGATTATTTAGTGCCCAGC  30 3287 876096 1477 1496  35424  35443 CCACTTCAGGAGAATGTATA  48 3288 876120 1696 1715  41929  41948 TATTTAGCTTATGATGAAAT  58 3289 876144 2400 2419  62021  62040 AGATCCACTATTCAGTAAGA  42 3290 876168 2874 2893  71717  71736 ACGCTGTAATACGGCATCTC  26 3291 876192 3289 3308  76423  76442 GATTAGCAATACAACTCATT  41 3292 876216 3805 3824  82150  82169 AGATGCTGATCTGATTATGG  46 3293 876240 4237 4256  86732  86751 GGATAGGCCAGTCTTTCACA  43 3294 876264 4731 4750  92154  92173 AATTGGCACATTTTTACGCT  41 3295 876288 5052 5071  98200  98219 AAAATACTGTGACATGTAGT  26 3296 876312 5444 5463 100433 100452 ACAACTTGGCCCAAAAGAAT 101 3297 876336 5690 5709 101328 101347 TCAGCCAAAATCAAGTCAGG  50 3298 876360 6293 6312 124924 124943 TAGAGTAGTAAACCAAATGA  82 3299 876384 6958 6977 N/A N/A CAGCTCCTTTAAGCTTAACA  73 3300 876408 7861 7880 146030 146049 CACATTTACTGGTAAGTATT  52 3301 876432 8818 8837 146987 147006 AATTATTACATAGGTATTTG  97 3302 876456 N/A N/A   4226   4245 GGTATACTACAACTAAAGGC  45 3303 876480 N/A N/A   6916   6935 CAAATATTGGCTGTGCAAAA  50 3304 876504 N/A N/A   8607   8626 TAAGCCAGATTGTATAAGAA  91 3305 876528 N/A N/A  11615  11634 ACACACCCTTTATGTACTGA  35 3306 876552 N/A N/A  14467  14486 CTACCTCTTAGTGGCCAAAG  58 3307 876576 N/A N/A  16784  16803 TAATTGAACTGTACTGTCAC  77 3308 876600 N/A N/A  19236  19255 CACTCATAACCCCACACCTT  68 3309 876624 N/A N/A  20923  20942 TGTTATATTGCTTACCTTTT  69 3310 876648 N/A N/A  24093  24112 TCAATGGCTCTATTTAACAC  74 3311 876672 N/A N/A  26696  26715 GTTTTAATTTTAACTATGAA  63 3312 876696 N/A N/A  29292  29311 CATTATATATATTATCTACT  94 3313 876720 N/A N/A  30992  31011 AAATTCAAACAAAATGTTAG  77 3314 876744 N/A N/A  33420  33439 CTTACTCAATAGTCACCTTC  51 3315 876768 N/A N/A  35168  35187 ACACATGTCATTTCCAATTT  38 3316 876792 N/A N/A  37410  37429 TAATTGTCTAAACTTTGAAC  72 3317 876816 N/A N/A  38923  38942 TCACATCAAACAGATCTCCC  68 3318 876840 N/A N/A  41323  41342 TGTAGCTGAACTATGCTAAA 118 3319 876864 N/A N/A  43234  43253 TGTATTAAAGTTTGAGTATA  77 3320 876888 N/A N/A  47312  47331 CCACAGTGAACATTCATGTC  39 3321 876912 N/A N/A  48595  48614 GTCCAAATATAAAGGCAAAA  36 3322 876936 N/A N/A  51297  51316 AGAAGTGGTAAGTTAAAAAG 101 3323 876960 N/A N/A  53567  53586 CCAGTATCTTGAATTCCTTA  38 3324 876984 N/A N/A  56680  56699 TATCAAAACATTAGAACTAT  86 3325 877008 N/A N/A  59803  59822 GAGAAAGTGAATCTGATAAA  48 3326 877032 N/A N/A  62335  62354 ATCTTTGGCTTAAGGTCCCT  54 3327 877056 N/A N/A  64117  64136 TGAAGATTAAAGTAAGCAGG  46 3328 877080 N/A N/A  66821  66840 AATAAGAATGGCCAATAAGA  97 3329 877104 N/A N/A  68820  68839 CAGGATAATTAAATCACTAA  89 3330 877128 N/A N/A  72024  72043 TCTTGAAGTGTACTGTAAGT  36 3331 877152 N/A N/A  73771  73790 AAATGTCTTGAAAGTTACAA  58 3332 877176 N/A N/A  75109  75128 ACCGAATGAGAATTAGGTGG  22 3333 877200 N/A N/A  77633  77652 ATAATTTTGTCTCTTCCAGA  61 3334 877224 N/A N/A  80461  80480 TATGGTACTAGCTCATAAAG  87 3335 877255 N/A N/A  84665  84684 TATGAGAAAGTAATAAGACC 103 3336 877279 N/A N/A  87867  87886 GTTTAGTCTCCATTCTAAAA  58 3337 877303 N/A N/A  90326  90345 AGGTGATTTATAAGTGCCAA  28 3338 877327 N/A N/A  91617  91636 GGTTATTTGTAAAATGTTAT  33 3339 877351 N/A N/A  93895  93914 CATTTTCCATGTGAAATATA  50 3340 877375 N/A N/A  95790  95809 AAATTCCTTTGTATTTCTCC  31 3341 877399 N/A N/A  97756  97775 GTCTCATCAATAATATATTC  46 3342 877423 N/A N/A 100944 100963 TGTTATTATATGGCAGACAT  66 3343 877447 N/A N/A 102748 102767 CTCAAATTTTGGACAACTTT  66 3344 877471 N/A N/A 105367 105386 ATGCTTTGTACCTTCAGGCC  39 3345 877495 N/A N/A 108045 108064 TTAGAAACACTTGAAGTCAT  61 3346 877519 N/A N/A 110743 110762 AATTAAAATGCCCCCAGGAT  74 3347 877543 N/A N/A 112384 112403 CTCTGTTTTTATCAGACATT  49 3348 877567 N/A N/A 115086 115105 GTTATTTAAAGTAAGGTTTC  52 3349 877591 N/A N/A 117552 117571 TTCATCTCAACCAGGTCTTA  67 3350 877615 N/A N/A 119913 119932 AGTTGCATATGGTTTAGGAG  29 3351 877639 N/A N/A 122135 122154 AATATTTACTTCAATATGGA  68 3352 877663 N/A N/A 124792 124811 CATCCAAGGAGGCATACACT  78 3353 877687 N/A N/A 127780 127799 TTAAAGGAAAAGTTAACCAG  75 3354 877711 N/A N/A 132127 132146 GATTGTTCCTCTCCCTCTCC  57 3355 877735 N/A N/A 134694 134713 TAATGACTAAATAGGAATCT  89 3356 877759 N/A N/A 139104 139123 GTAGATTTAGTGGTATTGAG  54 3357 877783 N/A N/A 141286 141305 ACTTTATATTAATTTCTTGT  67 3358 877807 N/A N/A 143430 143449 TACCATGTATTTCCCATTTT  61 3359 877831 N/A N/A 145069 145088 TTCTGTTAAAACTATATATT 128 3360

TABLE 45 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5’ to 3’) control NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  16  222 876028  732  751  18631  18650 ACTTAACAATATCATATAAT 116 3361 876052  840  859  21671  21690 ATTGCCACTCATGAGGACTT  23 3362 876076 1239 1258  29590  29609 CATAAGGAGATTATTTAGTG  51 3363 876100 1482 1501  35429  35448 TTCAGCCACTTCAGGAGAAT  36 3364 876124 1701 1720  41934  41953 AACCATATTTAGCTTATGAT  35 3365 876148 2452 2471  62073  62092 TGTCACCTTTCCCAATGCTT  37 3366 876172 2977 2996  73001  73020 GTGAATCATCTGAAGATAAT  79 3367 876196 3422 3441  76556  76575 TCTACCACATCAGTGAGGTT  46 3368 876220 3850 3869  82195  82214 GTTTCTCTACTCTAGACCAT  29 3369 876244 4313 4332  87217  87236 GTACTATAGAATTCCTCACG  33 3370 876268 4736 4755  92159  92178 AATTCAATTGGCACATTTTT  80 3371 876292 5070 5089  98218  98237 GAATTTTTCTAGGAGCTTAA  47 3372 876316 5450 5469 100439 100458 TGGTCCACAACTTGGCCCAA  45 3373 876340 5704 5723 101342 101361 TATTTCTAGGCAGGTCAGCC  62 3374 876364 6471 6490 126587 126606 AGGCCTTTCTTGAGGATTTT  56 3375 876388 7076 7095 137480 137499 GAGAAAATCTTTGTGCCACA  66 3376 876412 8045 8064 146214 146233 ACAGAATTTAAAATAAAGTT  64 3377 876436 8906 8925 147075 147094 TATCACAGGGAATTATCTGA 113 3378 876460 N/A N/A   4437   4456 ATCACCTTGGCCTATAATTT  73 3379 876484 N/A N/A   7124   7143 TTGCTTTTTACTAGCTTGCA  38 3380 876508 N/A N/A   9022   9041 GGCTCTTTCACATTTCGAAA  63 3381 876532 N/A N/A  11902  11921 TTTCCTACATAAACTTTTAT 137 3382 876556 N/A N/A  14858  14877 GTTGAGTACCTTCTTGTTTT  43 3383 876580 N/A N/A  17001  17020 TCTTGTGTATTATAATTATC  55 3384 876604 N/A N/A  19521  19540 AGCAATCATTGGTAGCATAC  17 3385 876628 N/A N/A  21334  21353 GTACTGAAAATGAAAGTCTG  79 3386 876652 N/A N/A  24857  24876 AAGGTAAGGTCTCAACCAGA  41 3387 876676 N/A N/A  27470  27489 TCATTGGCATGTTTACCATT  46 3388 876700 N/A N/A  29725  29744 CTAACAATAAAAGTTACGGT  49 3389 876724 N/A N/A  31409  31428 AATTTGGTTATAAAAGAGTA  94 3390 876748 N/A N/A  33425  33444 CAGGTCTTACTCAATAGTCA  32 3391 876772 N/A N/A  35704  35723 AGCATCAGGTTCAAAAGCAA  43 3392 876796 N/A N/A  37927  37946 CATTGTAGTTACTTTGTATA 100 3393 876820 N/A N/A  39204  39223 AAACTATGAATAGGACACCA  49 3394 876844 N/A N/A  41563  41582 CTGGAAGATTTTTATGCAAC  66 3395 876868 N/A N/A  45405  45424 CTCTCACAATGAGACAGGAT  48 3396 876892 N/A N/A  47401  47420 GGTGGAGAAATAAAAATATC 153 3397 876916 N/A N/A  49326  49345 GATGTCCCTTGTCTATGAGT  80 3398 876940 N/A N/A  51672  51691 GTCTTTGACCAAAATCTTCT  53 3399 876964 N/A N/A  54224  54243 CTATCTTGGTTTAATCAGCC  51 3400 876988 N/A N/A  57012  57031 ATATATTTTCATAGACTGAC  73 3401 877012 N/A N/A  59950  59969 CATCTTGAAACAGGAAACCC  90 3402 877036 N/A N/A  62729  62748 GCTTGAAAGTATAAAGAAAA  92 3403 877060 N/A N/A  64985  65004 GCTAAATAAAGGATCTTGTT  61 3404 877084 N/A N/A  67063  67082 TCTTAAGTGGGATACAAAAA  77 3405 877108 N/A N/A  69905  69924 AATTACAACTTCAATATTTC 117 3406 877132 N/A N/A  72455  72474 CAAAGTGAACCTGAGAATAA  86 3407 877156 N/A N/A  73937  73956 TCTGTTTCCATTGCCTGCCC  24 3408 877180 N/A N/A  75325  75344 ATTATTTTGCTTGCTCATTT  62 3409 877204 N/A N/A  78164  78183 TATCTCAGTATCAGGATGCC  36 3410 877228 N/A N/A  81375  81394 TACATAAACTTGCCTAATCT 120 3411 877235 N/A N/A  82381  82400 ATGGAAATCTGGATTTATAG  48 3412 877259 N/A N/A  84939  84958 TCAGAAAACAAAATCCTTCC  70 3413 877283 N/A N/A  87993  88012 CATTAAAAAATACCCAAATT 142 3414 877307 N/A N/A  90438  90457 TCAAACCATTATGCCAGAAT  34 3415 877331 N/A N/A  91722  91741 AATGTGAAACAGACACGCTA  53 3416 877355 N/A N/A  94450  94469 AATGTTTCAATATGCTCTTG  22 3417 877379 N/A N/A  95946  95965 ATTTTAAGCCTCCAAGTTTC 110 3418 877403 N/A N/A  98420  98439 CAAAATAAATGATACATGTC 104 3419 877427 N/A N/A 101435 101454 CATCCTAATTTTTATTCTCA  94 3420 877451 N/A N/A 103549 103568 AGCCAAAATGGCAACAGCTC  52 3421 877475 N/A N/A 105747 105766 TCATTCCACTTTGATTGTGT  40 3422 877499 N/A N/A 108438 108457 GGAATTTTCTTCAAATTTTG 102 3423 877523 N/A N/A 111233 111252 TCATAGGCACAGACAGAGGT  68 3424 877547 N/A N/A 112873 112892 ACTACAGTTGACCTATGGAC  74 3425 877571 N/A N/A 115802 115821 ATTGCAAGCATAAACAGATT  98 3426 877595 N/A N/A 118045 118064 ATGAATATTTTAACTATTTC  65 3427 877619 N/A N/A 119984 120003 GCTATTCATGGCTCTGTTGT  66 3428 877643 N/A N/A 122352 122371 GTTAGAATTTGGAATCACAG  42 3429 877667 N/A N/A 125287 125306 CAAATGTGGAGTTCTAACAG 106 3430 877691 N/A N/A 128589 128608 TGGACAAGGTTACTTGGGCA  55 3431 877715 N/A N/A 132782 132801 TTTATAAATGTCTCAGCTAG  72 3432 877739 N/A N/A 135635 135654 ATTGCTATAGCCACTACGGA 102 3433 877763 N/A N/A 140038 140057 CTAGAACTCCAAAAGTCCTA  76 3434 877787 N/A N/A 141378 141397 ACAAGCTAGACTATTGCAAT  55 3435 877811 N/A N/A 143863 143882 GAATATATTTTCTTCACCAT  62 3436 877835 N/A N/A 145294 145313 AAACTACCAATTAAAATTCC  80 3437

TABLE 46 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5’ to 3’) control NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  42  222 876029  733  752  18632  18651 CACTTAACAATATCATATAA  73 3438 876053  841  860  21672  21691 CATTGCCACTCATGAGGACT  29 3439 876077 1249 1268  29600  29619 TGTTTTGGTACATAAGGAGA  60 3440 876101 1483 1502  35430  35449 TTTCAGCCACTTCAGGAGAA  50 3441 876125 1702 1721  41935  41954 TAACCATATTTAGCTTATGA  56 3442 876149 2453 2472  62074  62093 CTGTCACCTTTCCCAATGCT  26 3443 876173 3064 3083  73600  73619 CTAGTGATGTAATATATTCT  32 3444 876197 3427 3446  76561  76580 GTTTCTCTACCACATCAGTG  38 3445 876221 3852 3871  82197  82216 CAGTTTCTCTACTCTAGACC  28 3446 876245 4315 4334  87219  87238 GAGTACTATAGAATTCCTCA  81 3447 876269 4741 4760  92164  92183 CGGGAAATTCAATTGGCACA  44 3448 876293 5071 5090  98219  98238 GGAATTTTTCTAGGAGCTTA  27 3449 876317 5451 5470 100440 100459 GTGGTCCACAACTTGGCCCA  72  152 876341 5745 5764 101383 101402 TGGAGCTTGTTCAAATTCCA  52  153 876365 6510 6529 129655 129674 TTCAGCTGAATTCAAAATGT  82 3450 876389 7174 7193 141535 141554 CCACTGTTATGATGTTGGAA  65 3451 876413 8085 8104 146254 146273 ATTTCTAGAAAAATCGACAA 115 3452 876437 8911 8930 147080 147099 TGTCCTATCACAGGGAATTA  81 3453 876461 N/A N/A   4590   4609 GTCTGTCAAGCCTCTCAACC  79 3454 876485 N/A N/A   7136   7155 TATCAAACCATTTTGCTTTT  79 3455 876509 N/A N/A   9076   9095 CAGATTTCTCTAGAATGAAT  67 3456 876533 N/A N/A  12031  12050 TGTGTCTATCTTCTTCACAA 119 3457 876557 N/A N/A  14909  14928 AGACTCTTAGTGCATGCCAT  46 3458 876581 N/A N/A  17076  17095 CCTTAGAAACACAGTAAACT  72 3459 876605 N/A N/A  19554  19573 AAAACAGAATATGAACCATT  48 3460  19584  19603 876629 N/A N/A  21340  21359 GGAAAAGTACTGAAAATGAA 134 3461 876653 N/A N/A  24869  24888 CAGACTCTCTGCAAGGTAAG  88 3462 876677 N/A N/A  27495  27514 CTTAAAGGAATAGTGCTTAG  71 3463 876701 N/A N/A  29875  29894 AATTACCAAATGACCCTTGA  73 3464 876725 N/A N/A  31897  31916 TGGTGTTTACTATGGGTTCC  28 3465 876749 N/A N/A  33427  33446 TGCAGGTCTTACTCAATAGT  75 3466 876773 N/A N/A  35778  35797 CACACAATAATTAGAAAAAC 106 3467 876797 N/A N/A  37999  38018 TCATGGCAACAAAAATAGAA 129 3468 876821 N/A N/A  39337  39356 TGTCAACTTTAAGGATAATC  35 3469 876845 N/A N/A  41680  41699 TAAATATAATGTGTAAGAAT 117 3470 876869 N/A N/A  45530  45549 CACCAACACTCACCATGAAT  62 3471 876893 N/A N/A  47579  47598 CCCTCAGGGACCTCTACTGA  59 3472 876917 N/A N/A  49662  49681 ATTTATCAGTGTCTACTTAG  68 3473 876941 N/A N/A  51782  51801 TTCATTTAGATGATGTTTTG  95 3474 876965 N/A N/A  54337  54356 ACTCTACTATAGAGATTCTA  95 3475 876989 N/A N/A  57276  57295 ATTTAATAATGTGTATTAAA 129 3476 877013 N/A N/A  59957  59976 TACAAACCATCTTGAAACAG  98 3477 877037 N/A N/A  62733  62752 ATGAGCTTGAAAGTATAAAG  83 3478 877061 N/A N/A  65104  65123 GTATCAGTGTCCTCACCTGG  84 3479 877085 N/A N/A  67064  67083 TTCTTAAGTGGGATACAAAA  81 3480 877109 N/A N/A  69996  70015 ATAGTCCTTAATGTTTGCAC  46 3481 877133 N/A N/A  72458  72477 TTTCAAAGTGAACCTGAGAA  83 3482 877157 N/A N/A  73938  73957 ATCTGTTTCCATTGCCTGCC  69 3483 877181 N/A N/A  75378  75397 CCTTGTCACAGTCTCTTCCA  56 3484 877205 N/A N/A  78262  78281 AAAACCATTAAATGATTAAT 148 3485 877229 N/A N/A  81468  81487 AACACACTCAAGATCCAATT  94 3486 877236 N/A N/A  82634  82653 ATCACACATAATTTGAAATG  91 3487 877260 N/A N/A  85112  85131 AGTATAATACACTGAAAGCT  86 3488 877284 N/A N/A  88019  88038 AGCTGTAAAAAAGTTAATAA  80 3489 877308 N/A N/A  90441  90460 TTTTCAAACCATTATGCCAG  77 3490 877332 N/A N/A  91728  91747 AAACTTAATGTGAAACAGAC  77 3491 877356 N/A N/A  94452  94471 GCAATGTTTCAATATGCTCT  13 3492 877380 N/A N/A  96049  96068 GAATGAAGCCAAGTGAATAA  82 3493 877404 N/A N/A  98444  98463 AGTGTCAGATGCAATGTTTT  92 3494 877428 N/A N/A 101447 101466 AGGAGAAAATTACATCCTAA  81 3495 877452 N/A N/A 104028 104047 AAGAGGAAATGTACCCTGTG  77 3496 877476 N/A N/A 105776 105795 CTCTCTCTCTTGCAAAATTA  74 3497 877500 N/A N/A 108554 108573 AATTCAAAAGGTCAAATTTT 105 3498 877524 N/A N/A 111239 111258 TTGTTTTCATAGGCACAGAC  35 3499 877548 N/A N/A 112899 112918 TTCAGTAATAAAAAGCTGGT  63 3500 877572 N/A N/A 115808 115827 CAAGGAATTGCAAGCATAAA  69 3501 877596 N/A N/A 118216 118235 GTCTAATATTACACAGCAAA  55 3502 877620 N/A N/A 119990 120009 ATATTTGCTATTCATGGCTC  54 3503 877644 N/A N/A 122379 122398 AGCATATTTTTTCTTGATAA  40 3504 877668 N/A N/A 125297 125316 TAAAAATCACCAAATGTGGA  85 3505 877692 N/A N/A 128599 128618 GATAATATGGTGGACAAGGT  38 3506 877716 N/A N/A 132876 132895 GATTCATTGATCTGAGGAGA  55 3507 877740 N/A N/A 135638 135657 TAAATTGCTATAGCCACTAC  72 3508 877764 N/A N/A 140071 140090 TTGCCGACCTAGGACTAAAA  53 3509 877788 N/A N/A 141480 141499 AAAAAATAGAAAGTCATCAC 128 3510 877812 N/A N/A 143888 143907 TTCCTCTTTCACATATACTT  77 3511 877836 N/A N/A 145295 145314 TAAACTACCAATTAAAATTC 139 3512

TABLE 47 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5’ to 3’) control NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  31  222 876030  734  753  18633  18652 GCACTTAACAATATCATATA  34 3513 876054  846  865  21677  21696 CCTGACATTGCCACTCATGA  38 3514 876078 1293 1312 N/A N/A AGCTGGGAAATGGCCATCTT  64 3515 876102 1484 1503  35431  35450 CTTTCAGCCACTTCAGGAGA  62 3516 876126 1704 1723  41937  41956 TTTAACCATATTTAGCTTAT  58 3517 876150 2454 2473  62075  62094 GCTGTCACCTTTCCCAATGC  31 3518 876174 3069 3088  73605  73624 AAGGTCTAGTGATGTAATAT  43 3519 876198 3457 3476 N/A N/A TTTTATTTCCTTCTAAAATG 113 3520 876222 3853 3872  82198  82217 GCAGTTTCTCTACTCTAGAC  25 3521 876246 4316 4335  87220  87239 TGAGTACTATAGAATTCCTC  46 3522 876270 4751 4770  92174  92193 CGGTCAATTACGGGAAATTC  45 3523 876294 5073 5092  98221  98240 CTGGAATTTTTCTAGGAGCT  13 3524 876318 5452 5471 100441 100460 TGTGGTCCACAACTTGGCCC  43 3525 876342 5787 5806 106478 106497 TCGGTAAACTGATCCAAAAC  63 3526 876366 6515 6534 129660 129679 ACTAATTCAGCTGAATTCAA  67 3527 876390 7179 7198 141540 141559 TACCACCACTGTTATGATGT  45 3528 876414 8090 8109 146259 146278 TGCAGATTTCTAGAAAAATC  43 3529 876438 8978 8997 147147 147166 TATAAATAAATTTAAAGTTT  96 3530 876462 N/A N/A   4609   4628 AAAGATTGAGATGCCTCATG  73 3531 876486 N/A N/A   7222   7241 GTAGGAGACCCCTTTCTACA  67 3532 876510 N/A N/A   9202   9221 AATGAAGCTAGAATAATAGA 118 3533 876534 N/A N/A  12064  12083 GAGTGATCTAATACACTCCA  93 3534 876558 N/A N/A  14962  14981 CCGTCAAAAAAAAAATACCT 129 3535 876582 N/A N/A  17310  17329 CTCGCTGCAATACACTTTGT  66 3536 876606 N/A N/A  19555  19574 CAAAACAGAATATGAACCAT  84 3537  19585  19604 876630 N/A N/A  21645  21664 TATTGCCTGAATTTAAAGAG  81 3538 876654 N/A N/A  25038  25057 ACTTTTAAATGCATTGTTGT  72 3539 876678 N/A N/A  27571  27590 TTTAAAGTTGAAACTCTTAA 124 3540 876702 N/A N/A  29941  29960 TGAATTAATATGGCATTTTA  86 3541 876726 N/A N/A  31920  31939 AAACAGAGGAGGAAAGTGAT 126 3542 876750 N/A N/A  33456  33475 TCAGAGGCAAAAAACAATAT  67 3543 876774 N/A N/A  35835  35854 CGTTGTGAAAGAGCAAAATT  50 3544 876798 N/A N/A  38037  38056 GTACAATTCAAACAAGAGAA 100 3545 876822 N/A N/A  39461  39480 GAAATACTGTATTCAAAACT  73 3546 876846 N/A N/A  41819  41838 GACTGTTACTTTCTAGAAAT  93 3547 876870 N/A N/A  45583  45602 GGCTAACTGGAACCAGTTAT  48 3548 876894 N/A N/A  47597  47616 GACTCTGCTTGTTGTAGTCC  68 3549 876918 N/A N/A  49701  49720 TAATGTATTGCATTGGTGCT  62 3550 876942 N/A N/A  51819  51838 TAAAAATTATAGTGCCATCC  51 3551 876966 N/A N/A  54764  54783 AATGCTACAGCAGAGCAGGC  45 3552 876990 N/A N/A  57307  57326 AACTATTGGCAAACATAGTA  76 3553 877014 N/A N/A  59967  59986 CATACAGACCTACAAACCAT  69 3554 877038 N/A N/A  62754  62773 CATAATATGTACAAAATACA 100 3555 877062 N/A N/A  65304  65323 AGTGATCCTGAATAATTAAC  94 3556 877086 N/A N/A  67065  67084 TTTCTTAAGTGGGATACAAA  66 3557 877110 N/A N/A  70097  70116 AATTCTTCCAGAGGAAGAAA 123 3558 877134 N/A N/A  72483  72502 ATTGGAGAATAGGTTAGAAC  64 3559 877158 N/A N/A  73939  73958 GATCTGTTTCCATTGCCTGC  44 3560 877182 N/A N/A  75408  75427 TGTCCAGTCATTGAATGCCG  30 3561 877206 N/A N/A  78354  78373 CTTTTAATAAAAGTGATGAT 115 3562 877230 N/A N/A  81470  81489 ACAACACACTCAAGATCCAA  68 3563 877237 N/A N/A  82682  82701 AACAGTTAAGAATAATTTGA 122 3564 877261 N/A N/A  85276  85295 CACTATTTGAAAAAATGTCT  81 3565 877285 N/A N/A  88051  88070 GACTGCCACTGTACTATTTG  45 3566 877309 N/A N/A  90454  90473 GCAATCAAATGAGTTTTCAA  66 3567 877333 N/A N/A  92392  92411 ATCAGTGGCCTATTAAAGAA  98 3568 877357 N/A N/A  94453  94472 TGCAATGTTTCAATATGCTC  34 3569 877381 N/A N/A  96103  96122 CAATACTCCAAAAACATGCA  52 3570 877405 N/A N/A  98870  98889 TTAGTTATGCATAGACAAAT  49 3571 877429 N/A N/A 101479 101498 ATATAATTATGAAATCTATT  95 3572 877453 N/A N/A 104214 104233 GAGTATGGATTGTCATGTCT  63 3573 877477 N/A N/A 105993 106012 ACAAAAAGTCTTTTTGAGGC  48 3574 877501 N/A N/A 108768 108787 TTACTACTATATATATATCA  72 3575 877525 N/A N/A 111286 111305 CATGTCAGTTGGTTAGAACT  62 3576 877549 N/A N/A 113456 113475 TATTACTACTTGCTATGAGG  55 3577 877573 N/A N/A 116029 116048 ATGAGCTCTCTAGGCAGACA  40 3578 877597 N/A N/A 118217 118236 AGTCTAATATTACACAGCAA  41 3579 877621 N/A N/A 120065 120084 TTTTTCCAGGTGGAAATATA 120 3580 877645 N/A N/A 122402 122421 ATTCAAAAACTATTTAAATG 118 3581 877669 N/A N/A 125328 125347 TAATGAGTACACAGTAATTC  54 3582 877693 N/A N/A 128602 128621 TCAGATAATATGGTGGACAA  53 3583 877717 N/A N/A 132890 132909 AGAGGCCCTACAAAGATTCA  92 3584 877741 N/A N/A 136288 136307 TCAACAATATAGAGAGGATC 113 3585 877765 N/A N/A 140272 140291 TGTATTTAATAGAAAATAGT 114 3586 877789 N/A N/A 141697 141716 TGAAGTGCAAAGATAATTCT 129 3587 877813 N/A N/A 144037 144056 CTGAGACAACCTATTGAGAG  67 3588 877837 N/A N/A 145342 145361 CATATCACTTGTAATTTTGA  43 3589

TABLE 48 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5’ to 3’) control NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  18  222 876031  736  755  18635  18654 ACGCACTTAACAATATCATA  22 3590 876055  867  886  21698  21717 TTCCACCACAATATTATAAC  42 3591 876079 1298 1317 N/A N/A CTATGAGCTGGGAAATGGCC  62 3592 876103 1485 1504  35432  35451 ACTTTCAGCCACTTCAGGAG  38 3593 876127 1723 1742  41956  41975 CATTCTTGAAACACTGTTTT  39 3594 876151 2456 2475  62077  62096 TGGCTGTCACCTTTCCCAAT  33 3595 876175 3153 3172  73689  73708 CTCCAGCTTTTCAAGATGCT  33 3596 876199 3529 3548  77278  77297 ATGAAATGTGGTTCTTACTA  35 3597 876223 3854 3873  82199  82218 TGCAGTTTCTCTACTCTAGA  23 3598 876247 4317 4336  87221  87240 ATGAGTACTATAGAATTCCT  48 3599 876271 4753 4772  92176  92195 TCCGGTCAATTACGGGAAAT  36 3600 876295 5074 5093  98222  98241 TCTGGAATTTTTCTAGGAGC  26  150 876319 5454 5473 100443 100462 AATGTGGTCCACAACTTGGC  49 3601 876343 5792 5811 106483 106502 GCTGCTCGGTAAACTGATCC  46 3602 876367 6601 6620 129746 129765 TGCTTGCATTCCTGCTGTTG  43 3603 876391 7218 7237 141579 141598 AACAGGGCTATTTTGCTTAG  54 3604 876415 8131 8150 146300 146319 TACATTACATGGGAAACTGT  43 3605 876439 9021 9040 147190 147209 AATACAGAAAATCTTTCATC 120 3606 876463 N/A N/A   4967   4986 ATCAGGCACTTCTGAACACC  51 3607 876487 N/A N/A   7241   7260 AGTGAGTATTAAAATGTCAG  47 3608 876511 N/A N/A   9214   9233 TGCTCCCCAAGTAATGAAGC  65 3609 876535 N/A N/A  12417  12436 GATTTTAATCCCTATGTTAT 115 3610 876559 N/A N/A  15046  15065 ACTTCAATATATTCCAGTGT  54 3611 876583 N/A N/A  17338  17357 TGCTATTCTGACTTTTGACA  87 3612 876607 N/A N/A  19605  19624 GTTAATGGTCACTTACAAAA  32 3613 876631 N/A N/A  21986  22005 GACACTCCTTTTAAAAGTCC  33 3614 876655 N/A N/A  25054  25073 TTCAGCAACCACTCTCACTT  60 3615 876679 N/A N/A  27604  27623 TTCATTGTGTAAAATAACTT  95 3616 876703 N/A N/A  29976  29995 ATCACAGATGGCTCTGCAAT  56 3617 876727 N/A N/A  32024  32043 ATAATAGACAATTTTACCAG  33 3618 876751 N/A N/A  33545  33564 AGAACATTTTACACACTATC  52 3619 876775 N/A N/A  35950  35969 CTATATAATCTTAGCATCTC  86 3620 876799 N/A N/A  38144  38163 CATTGAGGTAAATGAGTACA  83 3621 876823 N/A N/A  39741  39760 TTGATACCTAGAATGATACG  71 3622 876847 N/A N/A  42026  42045 ATAGTATAAATACAGAAAAC  84 3623 876871 N/A N/A  45585  45604 TTGGCTAACTGGAACCAGTT  63 3624 876895 N/A N/A  47882  47901 GGAAGGAAAAAACGAATACC  61 3625 876919 N/A N/A  49713  49732 ATCTTGAAATAGTAATGTAT  67 3626 876943 N/A N/A  52094  52113 TGGGACTTGAATATAAATGT  97 3627 876967 N/A N/A  54851  54870 TTGATAAGCAAAGTAGCCTT  34 3628 876991 N/A N/A  57309  57328 TAAACTATTGGCAAACATAG  79 3629 877015 N/A N/A  60005  60024 AGGTGATTTATGTTTTACTC  56 3630 877039 N/A N/A  62783  62802 TCAGAAGATGGTAACTTACC  85 3631 877063 N/A N/A  65433  65452 TAAGAGATACACCAGCAACT  91 3632 877087 N/A N/A  67067  67086 GGTTTCTTAAGTGGGATACA  45 3633 877111 N/A N/A  70265  70284 TACATAAGAAGAAATTTAAA 105 3634 877135 N/A N/A  72531  72550 ATTAACACAAAACAACCCTC  63 3635 877159 N/A N/A  73941  73960 CAGATCTGTTTCCATTGCCT  23 3636 877183 N/A N/A  75798  75817 AGCAAACCCCTACTTACACA  37 3637 877207 N/A N/A  78361  78380 TCTACAACTTTTAATAAAAG  85 3638 877231 N/A N/A  81545  81564 AAAGATAAATTTACACATAT  76 3639 877238 N/A N/A  82750  82769 AGAATTTTTATCCTTATACT  77 3640 877262 N/A N/A  85277  85296 CCACTATTTGAAAAAATGTC  41 3641 877286 N/A N/A  88222  88241 ATTCACTCCTAAATAAAATA  95 3642 877310 N/A N/A  90580  90599 ATGATCTCTAATAGATTAAA  76 3643 877334 N/A N/A  92439  92458 ACATGATTTGTCATGAACAC  19 3644 877358 N/A N/A  94604  94623 TAAGTGCTCTGGGTCACACT  53 3645 877382 N/A N/A  96108  96127 AGCACCAATACTCCAAAAAC  67 3646 877406 N/A N/A  98871  98890 ATTAGTTATGCATAGACAAA  83 3647 877430 N/A N/A 101490 101509 AATCTATGACAATATAATTA 102 3648 877454 N/A N/A 104219 104238 ATATGGAGTATGGATTGTCA  46 3649 877478 N/A N/A 106035 106054 ACTAGTTTTTATTCTACCTT  90 3650 877502 N/A N/A 108861 108880 CTAACATATACTCTTGGAGC  44 3651 877526 N/A N/A 111304 111323 AATCTTTTTTTTAATGCCCA  61 3652 877550 N/A N/A 113493 113512 TGATGGGTTCTAGAGCAGAA  38 3653 877574 N/A N/A 116095 116114 GCTAACACTTCATGACACAC  49 3654 877598 N/A N/A 118289 118308 AGCATCAAAAATTCTGTGCT  51 3655 877622 N/A N/A 120141 120160 GTGGTCCAGTCCACCTTCAT  61 3656 877646 N/A N/A 122515 122534 TTATGCTTCCCTTCTTAGAA  63 3657 877670 N/A N/A 125342 125361 AAAACATTCCAGGATAATGA  52 3658 877694 N/A N/A 128625 128644 TAAAACATGACAAGAGTTCT 124 3659 877718 N/A N/A 133009 133028 TCTTAATTTGGTAGTTAGAT  28 3660 877742 N/A N/A 136525 136544 GATGAAAGTAGGCCCCACTC  70 3661 877766 N/A N/A 140319 140338 TGTCAGAGAGCCACTACGCT  57 3662 877790 N/A N/A 141746 141765 TTCTCTATTCAGAGGCAGAA  61 3663 877814 N/A N/A 144077 144096 TTCAACTAGAGAATGCAACA  58 3664 877838 N/A N/A 145702 145721 AAAGATCCATCATAAAACAT 111 3665

TABLE 49 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5’ to 3’) control NO 780241 3714 3733  82059  82078 GCTCATATCTAAAGACCGCA  28  222 876027  730  749  18629  18648 TTAACAATATCATATAATCT   6 3666 876051  838  857  21669  21688 TGCCACTCATGAGGACTTCC  39 3667 876075 1237 1256  29588  29607 TAAGGAGATTATTTAGTGCC  61 3668 876099 1481 1500  35428  35447 TCAGCCACTTCAGGAGAATG  53 3669 876123 1700 1719  41933  41952 ACCATATTTAGCTTATGATG  25 3670 876147 2450 2469  62071  62090 TCACCTTTCCCAATGCTTAT  77 3671 876171 2936 2955  72960  72979 AAATCTTCATGATCAAAAAT  85 3672 876195 3338 3357  76472  76491 GTAGGATCTAAAACCACTGA  22 3673 876219 3840 3859  82185  82204 TCTAGACCATAAATATGCTT  29 3674 876243 4312 4331  87216  87235 TACTATAGAATTCCTCACGA  58 3675 876267 4735 4754  92158  92177 ATTCAATTGGCACATTTTTA  49 3676 876291 5069 5088  98217  98236 AATTTTTCTAGGAGCTTAAA 107 3677 876315 5448 5467 100437 100456 GTCCACAACTTGGCCCAAAA  30 3678 876339 5694 5713 101332 101351 CAGGTCAGCCAAAATCAAGT  37 3679 876363 6466 6485 126582 126601 TTTCTTGAGGATTTTCTTTC  75 3680 876387 7046 7065 137450 137469 ATTACATTTCTTTCCGTTGA  53 3681 876411 7998 8017 146167 146186 AAATTATCGGCCTTATAAAT  96 3682 876435 8867 8886 147036 147055 GGCCAAAGAATTTACCGAAA  48 3683 876459 N/A N/A   4386   4405 TTTTTAAGGCCCCCTTTAAA  95 3684 876483 N/A N/A   7028   7047 TTAGGTCTGTCACAAGCTCT  50 3685 876507 N/A N/A   8960   8979 CAGTCTGTTTACAAGATGCC  36 3686 876531 N/A N/A  11871  11890 TGAACAGTTGGTTTGTACAG  67 3687 876555 N/A N/A  14783  14802 GGACTGATGAGGACAATTCA  88 3688 876579 N/A N/A  16929  16948 AGGTGATCTATCCCATTCTG  67 3689 876603 N/A N/A  19458  19477 GTGGCTAAATTTCAAAGCCT  70 3690 876627 N/A N/A  21316  21335 TGGAAATGTAATGTATTGGT  56 3691 876651 N/A N/A  24654  24673 GCAGTTGGTTTAGACTCCCC  44 3692 876675 N/A N/A  27306  27325 AGGAAAAACTTTACCTGATA  83 3693 876699 N/A N/A  29666  29685 ATTTTCTATCATATAAAATC  93 3694 876723 N/A N/A  31361  31380 TAAAATTTTGTATATGTCAT 146 3695 876747 N/A N/A  33424  33443 AGGTCTTACTCAATAGTCAC  34 3696 876771 N/A N/A  35347  35366 CTGAAATTAACTGAGATTTT  84 3697 876795 N/A N/A  37878  37897 TATAAAAATTAATCTAAGTG  85 3698 876819 N/A N/A  39165  39184 CTGATTGAATAGCCACCAGA 110 3699 876843 N/A N/A  41526  41545 AAGCTCAGAGTTACTTGGAC  52 3700 876867 N/A N/A  45354  45373 GACGCGGCAACTGTGGCAAT  34 3701 876891 N/A N/A  47370  47389 ATGAATGATTACCATGTAAG  87 3702 876915 N/A N/A  49237  49256 TCCAACATCATATGACTGAT  62 3703 876939 N/A N/A  51525  51544 CAGTTTCTCACCCTGTGTCC  50 3704 876963 N/A N/A  54026  54045 AGTTACAAAAAATATTTCCT  79 3705 876987 N/A N/A  56923  56942 GAATTATATTTTGAAGGGAG  66 3706 877011 N/A N/A  59932  59951 CCATTTTATATTCTCTATTA  85 3707 877035 N/A N/A  62618  62637 TACATGTAAGCATATAAAAA 116 3708 877059 N/A N/A  64920  64939 CCTGATGGAATTTCAAAGTT  89 3709 877083 N/A N/A  67061  67080 TTAAGTGGGATACAAAAAGC  65 3710 877107 N/A N/A  69892  69911 ATATTTCTCTATCAAATACA  79 3711 877131 N/A N/A  72432  72451 GGCTCCCAATTTCCTCAACT  25 3712 877155 N/A N/A  73935  73954 TGTTTCCATTGCCTGCCCTC  62 3713 877179 N/A N/A  75295  75314 AATTGAAGGATTACCAAGTT  67 3714 877203 N/A N/A  78122  78141 TGCATGTTTAGTTTAAGACT  65 3715 877227 N/A N/A  81187  81206 GTTTTTACACAATGATCCAC  57 3716 877234 N/A N/A  82324  82343 TCATGAAATTGGTATTTAGA  73 3717 877258 N/A N/A  84886  84905 AGAGATTTTAGGCAGAAGAG  68 3718 877282 N/A N/A  87961  87980 TGTATGCAGCCAATTACATG  81 3719 877306 N/A N/A  90436  90455 AAACCATTATGCCAGAATGC  54 3720 877330 N/A N/A  91673  91692 CTTTTGGATATTATTATATT  76 3721 877354 N/A N/A  94268  94287 AATAATTTTAGGAACTCGGG  85 3722 877378 N/A N/A  95893  95912 ACATTATCTTGACTTTATCA  41 3723 877402 N/A N/A  98345  98364 TAGACTACAGTTAGTTTGAC  49 3724 877426 N/A N/A 101401 101420 ATTACCTAGGAGAAACTCTG  66 3725 877450 N/A N/A 103499 103518 TTCTGTAAATGAACATGGGA  62 3726 877474 N/A N/A 105725 105744 CTCTCCTGTTCAGAAACAAA 114 3727 877498 N/A N/A 108194 108213 GAGGGCGAGGAAACTAACTC  66 3728 877522 N/A N/A 111004 111023 CACCATTCCCTTAGTTTGCC  38 3729 877546 N/A N/A 112841 112860 AAGTGCATGAGTCCACATAT  81 3730 877570 N/A N/A 115680 115699 TAGAGTCAAGGACCTGGTGG  62 3731 877594 N/A N/A 117784 117803 CTTCTGTTTGAGTATATAAT  83 3732 877618 N/A N/A 119917 119936 TTAGAGTTGCATATGGTTTA  41 3733 877642 N/A N/A 122346 122365 ATTTGGAATCACAGGCTCTT  66 3734 877666 N/A N/A 125137 125156 TTATGCACTAAACAAAAAAA 106 3735 877690 N/A N/A 128267 128286 TGGGACCCCAAAGGACTGCA  54 3736 877714 N/A N/A 132254 132273 TTTATTTAATTTTCAGCAAT  78 3737 877738 N/A N/A 135518 135537 ATATCAAAGGGATTCCTATA 113 3738 877762 N/A N/A 139971 139990 CCTCTCAGTCGGTGTGTACT 102 3739 877786 N/A N/A 141372 141391 TAGACTATTGCAATTATTTC  87 3740 877810 N/A N/A 143858 143877 TATTTTCTTCACCATGTTCA  97 3741 877834 N/A N/A 145268 145287 TACCATATGTAATATTTTCT  57 3742

TABLE 50 Percent control of human LRRK2 RNA with 5-10-5 MOE gapmers with mixed internucleoside linkages SEQ SEQ SEQ SEQ ID ID ID ID NO: 1 NO: 1 NO: 2 NO: 2 LRRK2 SEQ Compound Start Stop Start Stop % ID Number Site Site Site Site Sequence (5’ to 3’) control NO 780241 3714 3733 82059 82078 GCTCATATCTAAAGACCGCA  24  222 803629 N/A N/A 81591 81610 AAGCCATAGTGTTTGAAGGA  34 1791 876014 340 359 87848 87867 CCTGCTGCACACTCGCGACT  48 3743 876038 823 842 3731 3750 CTTCCACATTATTGCAAGGA  41 3744 876062 1022 1041 27997 28016 GCTGCATTCTCTGGGTACTG  28 3745 876086 1465 1484 35412 35431 AATGTATATGCTTCTGCATT  77 3746 876110 1494 1513 35441 35460 TTTACAGCCACTTTCAGCCA  63 3747 876134 2047 2066 N/A N/A ATCCTTTAGTCTGTATTTCA  83 3748 876158 2711 2730 65549 65568 GACAGCACATCTTCAGAAAA  64 3749 876182 3221 3240 76355 76374 AAATGTGTCAAACTCTTCAG  52 3750 876206 3747 3766 82092 82111 TGCGGGACCTGGTAGGTACT  57 3751 876230 3968 3987 83963 83982 CCCATTTCATTGGGAAAGGA  45 3752 876254 4520 4539 88621 88640 AGTTCCTTGGTGATTTTACT  45 3753 876278 4919 4938 93380 93399 ATTTTACAAAGCCACTTGGG  74 3754 876302 5195 5214 99201 99220 GGCATTTCATATAGTCGGAT  26 3755 876326 5644 5663 101282 101301 GCCTTGGTTGATCTGGATTT  32 3756 876350 6028 6047 113225 113244 GTGCAATCCTGTGCTGTAGG  42 3757 876374 6694 6713 N/A N/A TACTATCAGCAACTTCCTCA 100 3758 876398 7439 7458 143087 143106 CGTATAAGTCGACGAGTTGA  98 3759 876422 8442 8461 146611 146630 TCAGGGTATCCACATTCAAA  69 3760 876446 N/A N/A   3734   3753 TTACCTGCTGCACACTCGCG  63 3761 876470 N/A N/A   5242   5261 TCCTTATTTTCCAGCATACT  57 3762 876494 N/A N/A   7823   7842 TCTCTCTAAGAGAGAAGGTT  64 3763 876518 N/A N/A  10777  10796 CTTCATGGTTTGAATTCAAA  38 3764 876542 N/A N/A  13175  13194 AAATCATCAATTGTATACCT  70 3765 876566 N/A N/A  15815  15834 CTCAATCAGTACTTCTAGCC  79 3766 876590 N/A N/A  17963  17982 AGTTTATCTAGCTTGAGAAT  67 3767 876614 N/A N/A  20012  20031 AAACCATGGCCTTTCTCTAT  65 3768 876638 N/A N/A  22763  22782 CCAAAACATTATTATCCAGA  58 3769 876662 N/A N/A  26068  26087 AGAAATTTGGGTTCTCAGCC  64 3770 876686 N/A N/A  28077  28096 AAATGCCTCTGTAAGAATCC  81 3771 876710 N/A N/A  30722  30741 AAGTGAGGAGAAGAGAATGG  96 3772 876734 N/A N/A  32675  32694 TCTAAAGGTGCCCCAACAGA  71 3773 876758 N/A N/A  34015  34034 ATCACATACACATTCTAAAA  68 3774 876782 N/A N/A  36424  36443 ATAGATTAGTTAGACTGATG  48 3775 876806 N/A N/A  38547  38566 TTCTGCTTGAAATGTCTTCC  78 3776 876830 N/A N/A  40757  40776 TCTTTGTTCTATCACTTGAG  72 3777 876854 N/A N/A  42910  42929 CCTTCTTCTCTTTTTCATAC  42 3778 876878 N/A N/A  46658  46677 TAAAAATTTAGTCCTTCATC 115 3779 876902 N/A N/A  48098  48117 AGGGTGCATAGTCTGTAGGT  52 3780 876926 N/A N/A  50310  50329 CTGTTTGGCAGGCAAGGCCA 114 3781 876950 N/A N/A  52848  52867 ATTCTAAATCCTGAATTCAA 102 3782 876974 N/A N/A  55881  55900 AGGATGTTCATTTAACTATA  53 3783 876998 N/A N/A  57829  57848 GAATATGGAAAGAGGAATAA  94 3784 877022 N/A N/A  61188  61207 TCCATCAGTTACTGTGCTAA  58 3785 877046 N/A N/A  63238  63257 GAAGAGAGAATTTAGAGCTA  81 3786 877070 N/A N/A  66210  66229 AAAGCCCCTCACTCCATTTT  60 3787 877094 N/A N/A  67516  67535 AAGTTAGTTGATTAAAAATT 120 3788 877118 N/A N/A  71000  71019 ATAAATTTGGCTGGCAATAA  76 3789 877142 N/A N/A  72845  72864 GTTAATGGTATTTATAATTA  86 3790 877166 N/A N/A  74324  74343 ATTTTCAGAGAGCTATCCTA 103 3791 877190 N/A N/A  76592  76611 CTTTCTTACCCTTCTAAAAT  71 3792 877214 N/A N/A  79053  79072 CTGAGATGACACACTGACCA  50 3793 877245 N/A N/A  83601  83620 CTCTTCAAGACATTGAAAGT  81 3794 877269 N/A N/A  86919  86938 GAAATGAAGGGCTTTGGAAT  76 3795 877293 N/A N/A  89053  89072 ATAAGAAGTTGAATCAGAAA  99 3796 877317 N/A N/A  91034  91053 CTCTTAACCCAGAGAATTAG  82 3797 877341 N/A N/A  93061  93080 ACAGAGCATATTTCACACAT  42 3798 877365 N/A N/A  95209  95228 CCACAGAATCTTCAGGAATT  45 3799 877389 N/A N/A  96646  96665 TTGGATAAATTATTCAACCT  70 3800 877413 N/A N/A  99821  99840 TGATCATGCTAAACGCAAAA  90 3801 877437 N/A N/A 102050 102069 GAATATTGAAACATGGTTAC  48 3802 877461 N/A N/A 104931 104950 TCTTGGTATTCTCTCATTCT  46 3803 877485 N/A N/A 106787 106806 TTACAACACACTATGTATCA  86 3804 877509 N/A N/A 109992 110011 ATTAAACCAATATACCAAGG  60 3805 877533 N/A N/A 111782 111801 GCAATTCAAAAAAAGTCCGA  58 3806 877557 N/A N/A 114063 114082 TGAGAGAAATTGTTAGAAGC  85 3807 877581 N/A N/A 116850 116869 TTTATAGAACACAGACTCTT  88 3808 877605 N/A N/A 119162 119181 AGGGAGGTAAGATTCCACAG  62 3809 877629 N/A N/A 121067 121086 CATATGTCAGAGGGTCCTAA  63 3810 877653 N/A N/A 123315 123334 TTTGCTAAAATTATCTGTGC  65 3811 877677 N/A N/A 126752 126771 GATGGTGAAAATTATAGGAG  50 3812 877701 N/A N/A 129290 129309 AAAAACCCTTGGGCCAACAA  71 3813 877725 N/A N/A 133380 133399 CCCTGCTGTGATAGGCTTGA  51 3814 877749 N/A N/A 138071 138090 TTGAAAGAGGTTTATATTAA  95 3815 877773 N/A N/A 140699 140718 GGTGTCACTGTCATATTATA  60 3816 877797 N/A N/A 142490 142509 ATAGTCTAATTCATGACAAA 102 3817 877821 N/A N/A 144612 144631 CTATGTAGGCCCTAGGCTAG  73 3818

Example 5: Effect of 5-10-5 MOE Gapmers with Phosphorothioate Internucleoside Linkages on Human LRRK2 RNA Expression In Vitro, Multiple Doses

Modified oligonucleotides selected from Example 1 above were tested at various doses in SH-SY5Y cells. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 1.125 μM, 2.250 μM, 4.500 μM, 9.000 μM, and 18.000 μM concentrations of modified oligonucleotide, as specified in the tables below. After a treatment period of approximately 24 hours, total RNA was isolated from the cells and LRRK2 RNA levels were measured by quantitative real-time PCR. Human LRRK2 primer probe set RTS3133_MGB (described herein in Example 1) was used to measure RNA levels. LRRK2 RNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented in the table below as percent LRRK2 RNA levels relative to untreated control cells. As illustrated in the tables below, LRRK2 RNA levels were reduced in a dose-dependent manner in modified oligonucleotide-treated cells. IC50 was calculated using the “log(inhibitor) vs. response—variable slope (4 parameters)” formula using Prism6 software.

TABLE 51 Dose-dependent reduction of human LRRK2 RNA expression in SH-SY5Y cells LRRK2 expression (% control) Compound 1.125 2.250 4.500 9.000 18.000 IC₅₀ Number μM μM μM μM μM (μM) 438387 81 43 30 18 14 2 438429 119 109 116 89 81 31 438432 110 78 64 42 15 7 438543 94 85 69 44 42 10 438565 92 80 80 66 53 22 438569 94 79 65 51 47 12 438586 98 85 52 38 27 6 438587 91 80 58 43 32 7 438595 86 66 41 35 25 4 438597 45 39 37 32 18 n/a* 438602 59 73 50 30 33 4 438622 109 115 100 92 85 40 438625 110 108 96 94 81 36 422428 75 57 35 27 20 3 422433 75 56 32 18 15 3 422450 81 97 87 71 66 51 422451 74 52 40 29 26 3 422461 89 65 44 30 25 4 438538 72 54 33 20 16 3 438544 65 39 28 18 12 2 438545 90 60 37 15 13 3 438548 89 65 38 20 16 4 438550 95 78 59 34 15 6 438560 56 41 30 22 23 1 438588 65 57 49 26 17 3 438652 109 94 74 54 53 15 *IC₅₀ value could not be calculated

Example 6: Effect of 5-10-5 MOE Gapmers with Mixed Internucleoside Linkages on Human LRRK2 RNA Expression In Vitro, Multiple Doses

Modified oligonucleotides selected from Examples 2 and 3 above were tested at various doses in SH-SY5Y cells. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 0.333 μM, 1.000 μM, 3.000 μM, and 9.000 μM concentrations of modified oligonucleotide, as specified in the tables below. After a treatment period of approximately 24 hours, total RNA was isolated from the cells and LRRK2 RNA levels were measured by quantitative real-time PCR. Human LRRK2 primer probe set RTS3132 (described hereinabove in Example 2) was used to measure RNA levels. LRRK2 RNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented in the table below as percent LRRK2 RNA levels relative to untreated control cells. As illustrated in the tables below, LRRK2 RNA levels were reduced in a dose-dependent manner in modified oligonucleotide-treated cells. IC50 was calculated using the “log(inhibitor) vs. response—variable slope (4 parameters)” formula using Prism6 software.

TABLE 52 Dose-dependent reduction of human LRRK2 expression in SH-SY5Y cells LRRK2 expression (% control) Compound 0.333 1.000 3.000 9.000 IC₅₀ Number μM μM μM μM (μM) 693423 62 46 45 13 0.9 693428 58 45 34 13 0.7 693430 68 28 32 26 0.6 725607 66 42 30 21 0.8 725608 54 44 36 40 0.4 780148 80 67 51 19 2.2 780162 56 35 29 19 0.4 780164 43 24 21 24 0.07 780166 60 51 26 18 0.8 780189 60 37 22 31 0.5 780202 70 42 36 20 0.9 780205 68 44 32 25 0.9 780210 62 56 31 25 1.0 780219 75 52 24 31 1.2 780236 42 34 29 19 0.1 780241 67 47 18 5 0.8 780243 37 41 26 25 n/a* 780254 68 37 35 19 0.8 780284 66 44 26 19 0.8 *IC₅₀ value cannot be calculated

TABLE 53 Dose-dependent reduction of human LRRK2 expression in SH-SY5Y cells LRRK2 expression (% control) Compound 0.333 1.000 3.000 9.000 IC₅₀ Number μM μM μM μM (μM) 780254 61 45 23 17 0.7 780321 66 59 46 25 1.6 780347 55 47 43 47 0.8 780430 82 70 55 33 3.5 780442 80 81 43 31 3.0 780455 92 61 47 21 2.2 780461 74 90 72 40 7.3 780499 74 67 36 36 2.2 780535 86 71 75 63 >60 780549 56 31 19 2 0.4 780551 93 65 26 35 1.9 780602 52 41 27 17 0.4 780624 71 52 37 27 1.3 780649 67 40 29 12 0.7 780670 85 71 55 31 3.4 780685 73 43 29 15 0.9 780700 96 61 36 24 2.0 780704 84 86 45 37 3.8 780706 94 72 66 42 6.1

Example 7: Effect of 5-10-5 MOE Gapmers with Mixed Internucleoside Linkages on Human LRRK2 RNA Expression In Vitro, Multiple Doses

Modified oligonucleotides selected from Example 4 above were tested at various doses in SH-SY5Y cells. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 0.296, 0.888, 2.666, and 8.000 μM concentrations of modified oligonucleotide, as specified in the tables below. After a treatment period of approximately 24 hours, total RNA was isolated from the cells and LRRK2 RNA levels were measured by quantitative real-time PCR. Human LRRK2 primer probe set RTS3132 (described herein in Example 2) was used to measure RNA levels. LRRK2 RNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented in the table below as percent LRRK2 RNA levels relative to untreated control cells. As illustrated in the tables below, LRRK2 RNA levels were reduced in a dose-dependent manner in modified oligonucleotide-treated cells. 1050 was calculated using the “log(inhibitor) vs. response—variable slope (4 parameters)” formula using Prism6 software.

TABLE 54 Dose-dependent reduction of human LRRK2 expression in SH-SY5Y cells LRRK2 expression (% control) Compound 0.296 0.888 2.666 8.000 IC₅₀ Number μM μM μM μM (μM) 780254 58 36 30 15 0.5 802655 103 90 87 20 5.0 802678 51 68 25 5 0.7 802685 110 82 43 13 2.3 802686 147 115 70 29 4.8 802688 87 67 40 15 1.7 802689 85 69 52 6 2.0 802700 163 84 29 29 2.0 802731 155 89 43 40 3.7 802746 120 78 65 18 3.5 802748 116 82 36 12 2.1 802758 119 71 31 5 1.7 802769 87 81 39 38 2.9 802778 97 53 56 30 2.6 802780 92 53 34 22 1.4 802784 84 82 42 26 2.5 802832 116 62 94 31 6.0 802888 58 54 26 10 0.7 802915 80 50 28 10 1.0

TABLE 55 Dose-dependent reduction of human LRRK2 expression in SH-SY5Y cells LRRK2 expression (% control) Compound 0.296 0.888 2.666 8.000 IC₅₀ Number μM μM μM μM (μM) 780254 76 56 26 12 1.0 802845 127 100 43 13 1.0 802911 77 44 27 11 0.8 802924 184 159 59 18 n/a* 802934 158 108 93 47 7.6 802949 113 69 33 No signal 1.7 802962 128 150 93 27 6.1 802966 171 130 17 31 n/a* 802974 120 71 36 13 1.9 803000 106 158 57 36 4.9 803021 80 112 75 70 22.1  803045 87 68 54 32 3.0 803046 70 69 28 14 1.2 803054 104 114 116 45 n/a* 803064 60 80 62 26 3.1 803065 101 89 27 55 4.0 803075 94 56 53 10 1.8 803112 90 37 27 11 0.9 803122 74 63 26 27 1.3 *IC₅₀ value cannot be calculated

TABLE 56 Dose-dependent reduction of human LRRK2 expression in SH-SY5Y cells LRRK2 expression (% control) Compound 0.296 0.888 2.666 8.000 IC₅₀ Number μM μM μM μM (μM) 780254 57 43 30 10 0.5 803102 76 76 46 28 2.4 803123 103 110 60 30 4.2 803172 104 87 82 46 7.3 803177 138 98 72 41 5.9 803181 142 84 86 50 8.0 803272 105 94 68 47 6.6 803285 87 80 56 38 4.1 803359 102 81 105 69 n/a* 803386 81 65 28 24 1.4 803436 116 97 59 81 n/a* 803470 60 61 25 44 1.1 803503 71 50 61 50 8.4 803517 75 48 58 22 1.7 803519 80 59 43 52 3.9 803571 65 57 36 26 1.1 803595 66 62 34 25 1.2 803603 86 65 59 29 3.0 803604 50 32 52 22 0.2 *IC₅₀ value cannot be calculated

TABLE 57 Dose-dependent reduction of human LRRK2 expression in SH-SY5Y cells LRRK2 expression (% control) Compound 0.296 0.888 2.666 8.000 IC₅₀ Number μM μM μM μM (μM) 780254 54 45 18 22 0.4 780620 120 87 77 37 5.7 780624 133 66 38 62 5.5 803541 110 86 40 16 2.3 803628 140 77 57 15 3.0 803629 78 31 40 15 0.8 803640 116 125 81 39 6.4 803645 123 117 59 33 4.5 803665 154 121 68 48 6.8 803680 87 71 39 27 2.1 803682 94 64 31 17 1.5 803686 79 69 54 21 2.3 803744 85 50 29 20 1.1 803745 91 75 55 24 2.9 803769 60 79 48 19 1.9 803770 43 38 25 5 0.2 803771 49 47 20 11 0.4 803773 73 54 28 28 1.1 803782 75 61 22 16 1.1

Example 8: Effect of 5-10-5 MOE Gapmers with Mixed Internucleoside Linkages on Human LRRK2 RNA Expression In Vitro, Multiple Doses

Modified oligonucleotides selected from Example 4 above were tested at various doses in SH-SY5Y cells. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 0.444, 1.333, 4.000, and 12.000 μM concentrations of modified oligonucleotide, as specified in the tables below. After a treatment period of approximately 24 hours, total RNA was isolated from the cells and LRRK2 RNA levels were measured by quantitative real-time PCR. Human LRRK2 primer probe set RTS3132 (described herein in Example 2) was used to measure RNA levels. LRRK2 RNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented in the table below as percent LRRK2 RNA levels relative to untreated control cells. As illustrated in the tables below, LRRK2 RNA levels were reduced in a dose-dependent manner in modified oligonucleotide-treated cells. 1050 was calculated using the “log(inhibitor) vs. response—variable slope (4 parameters)” formula using Prism6 software.

TABLE 58 Dose-dependent reduction of human LRRK2 expression in SH-SY5Y cells LRRK2 expression (% control) Compound 0.444 1.333 4.000 12.000 IC₅₀ Number μM μM μM μM (μM) 780241 57 29 9 3 0.6 876032 80 56 25 12 1.6 876033 65 45 45 8 1.3 876035 65 59 35 17 1.6 876200 105 49 29 17 1.9 876201 83 84 45 22 3.8 876204 58 38 22 14 0.7 876224 74 48 41 15 1.6 876274 70 48 26 16 1.2 876298 60 47 42 28 1.2 876611 71 52 27 16 1.4 876683 79 58 23 27 1.8 876706 80 57 43 17 2.2 876850 89 64 37 16 2.4 876899 42 29 18 9 0.3 877113 53 44 34 10 0.7 877160 88 57 29 14 1.9 877239 115 93 59 31 6.1 877722 72 43 38 28 1.5

TABLE 59 Dose-dependent reduction of human LRRK2 expression in SH-SY5Y cells LRRK2 expression (% control) Compound 0.444 1.333 4.000 12.000 IC₅₀ Number μM μM μM μM (μM) 780241 54 37 41 19 n/a* 803629 90 60 31 31 2.5 876062 62 38 16 7 0.8 876084 114 89 42 18 3.7 876109 84 58 59 40 5.6 876156 80 68 28 31 2.5 876180 79 53 41 15 1.9 876181 73 51 31 33 1.7 876276 93 51 19 11 1.5 876301 55 41 32 7 0.7 876302 47 25 21 7 0.3 876326 66 50 35 12 1.3 876900 63 42 21 13 0.9 876901 63 56 36 29 1.6 877068 66 42 17 5 0.9 877292 53 34 16 28 0.4 877364 71 53 28 31 1.6 877388 57 56 34 37 1.3 877748 71 58 40 24 2.0 *IC₅₀ value cannot be calculated

TABLE 60 Dose-dependent reduction of human LRRK2 expression in SH-SY5Y cells LRRK2 expression (% control) Compound 0.444 1.333 4.000 12.000 IC₅₀ Number μM μM μM μM (μM) 780241 87 35 22 14 1.2 876038 68 39 40 32 1.3 876041 78 60 31 23 2.0 876042 52 34 25 12 0.5 876088 77 61 56 20 3.1 876089 80 76 48 15 3.2 876090 73 53 38 22 1.8 876185 55 52 32 15 0.9 876186 52 33 23 11 0.5 876282 53 35 25 11 0.5 876328 79 60 25 15 1.7 876401 83 60 52 42 5.1 876518 75 75 39 22 2.8 876713 61 59 50 19 1.9 876905 75 58 42 25 2.3 877098 82 54 34 24 2.0 877170 71 60 35 24 1.9 877392 68 48 31 23 1.3 877753 67 55 26 22 1.4

TABLE 61 Dose-dependent reduction of human LRRK2 expression in SH-SY5Y cells LRRK2 expression (% control) Compound 0.444 1.333 4.000 12.000 IC₅₀ Number μM μM μM μM (μM) 780241 70 44 39 18 1.4 876019 67 45 28 11 1.1 876020 67 55 49 25 2.2 876066 60 62 36 19 1.5 876139 78 37 39 10 1.3 876140 80 47 36 14 1.6 876255 72 39 33 27 1.2 876260 70 46 22 29 1.2 876261 33 25 18 4 n/a* 876283 75 60 29 13 1.7 876284 48 35 35 18 n/a* 876303 48 21 32 2 0.3 876499 66 72 42 26 2.7 876735 67 43 28 7 1.0 876927 63 42 37 41 1.2 877119 61 31 35 4 0.7 877246 78 58 43 34 2.9 877370 69 58 46 40 3.3 877635 77 82 46 24 3.7 *IC₅₀ value cannot be calculated

TABLE 62 Dose-dependent reduction of human LRRK2 expression in SH-SY5Y cells LRRK2 expression (% control) Compound 0.444 1.333 4.000 12.000 IC₅₀ Number μM μM μM μM (μM) 780241 62 42 16 23 0.8 780624 70 37 21 6 0.9 803640 80 34 53 43 3.0 876141 66 50 30 17 1.2 876143 70 55 38 29 1.9 876165 110 74 54 18 4.1 876166 64 53 34 27 1.4 876189 62 33 24 22 0.7 876190 44 27 34 10 0.2 876213 71 50 37 12 1.5 876237 52 41 20 15 0.6 876262 59 37 21 13 0.7 876263 61 36 36 23 0.8 876285 68 62 31 23 1.8 876286 69 67 33 21 2.0 876645 94 59 47 17 2.8 876766 67 37 26 13 0.9 876790 58 41 33 13 0.8 877222 68 48 32 20 1.3

TABLE 63 Dose-dependent reduction of human LRRK2 expression in SH-SY5Y cells LRRK2 expression (% control) Compound 0.444 1.333 4.000 12.000 IC₅₀ Number μM μM μM μM (μM) 780241 71 54 41 27 2.0 876072 73 57 40 29 2.2 876073 72 52 24 25 1.4 876095 101 80 61 31 5.8 876097 55 44 42 24 n/a* 876168 64 45 21 9 0.9 876215 88 62 37 13 2.3 876288 75 62 28 6 1.7 876289 73 65 41 20 2.3 876335 77 75 43 25 3.2 876527 90 73 41 21 3.1 876769 78 67 41 31 1.5 877176 75 55 41 7 1.8 877303 61 45 23 19 0.8 877328 64 38 27 12 0.9 877375 82 68 47 28 3.5 877615 58 61 33 21 1.4 877616 75 50 25 19 1.4 877806 83 76 50 26 4.0 *IC₅₀ value can't be calculated

TABLE 64 Dose-dependent reduction of human LRRK2 expression in SH-SY5Y cells LRRK2 expression (% control) Compound 0.444 1.333 4.000 12.000 IC₅₀ Number μM μM μM μM (μM) 780241 66 53 29 24 1.4 876050 83 58 52 17 2.8 876052 72 48 53 17 2.0 876053 75 47 36 20 1.6 876098 95 59 38 16 2.4 876149 71 52 28 20 1.4 876218 79 61 44 17 2.4 876220 68 43 39 18 1.3 876221 48 29 16 9 0.4 876293 72 54 21 17 1.3 876337 85 90 59 19 4.9 876362 86 73 54 26 4.2 876385 81 62 36 20 2.3 876604 48 27 23 16 0.3 876725 66 50 39 35 1.7 876890 76 57 37 21 2.0 877156 80 58 44 28 2.7 877355 71 46 42 14 1.5 877356 49 41 24 29 0.3

TABLE 65 Dose-dependent reduction of human LRRK2 expression in SH-SY5Y cells LRRK2 expression (% control) Compound 0.444 1.333 4.000 12.000 IC₅₀ Number μM μM μM μM (μM) 780241 75 62 42 15 2.2 876027 87 76 74 54 n/a* 876030 75 60 44 18 2.3 876031 69 44 43 13 1.4 876123 68 48 28 27 1.3 876150 82 55 48 27 2.8 876195 77 51 31 45 2.4 876219 77 65 46 24 2.9 876222 102 68 54 21 3.9 876223 74 58 41 16 2.0 876294 44 25 16 10 0.3 876295 71 48 51 36 2.7 876315 75 58 46 41 3.7 877131 83 67 43 23 2.9 877159 68 59 41 24 2.0 877182 104 88 70 19 5.9 877334 93 87 51 22 4.4 877357 97 84 51 25 4.5 877718 73 57 51 32 3.0 *IC₅₀ value cannot be calculated

TABLE 66 Dose-dependent reduction of human LRRK2 expression in SH-SY5Y cells LRRK2 expression (% control) Compound 0.444 1.333 4.000 12.000 IC₅₀ Number μM μM μM μM (μM) 780241 63 36 24 23 0.8 803627 76 52 30 10 1.4 876008 59 56 33 31 1.3 876011 90 66 45 29 3.4 876034 102 67 39 28 3.2 876081 80 69 56 29 4.2 876106 64 43 31 23 1.0 876203 60 40 23 7 0.8 876225 77 54 41 32 2.4 876249 81 69 37 33 3.1 876321 74 63 43 21 2.4 876540 90 69 44 22 3.1 876704 83 73 49 47 6.8 876731 70 49 39 40 2.1 877088 77 61 38 31 2.6 877112 65 52 28 17 1.2 877161 91 61 62 19 3.8 877289 73 55 34 20 1.7 877337 71 57 31 22 1.7

TABLE 67 Dose-dependent reduction of human LRRK2 expression in SH-SY5Y cells LRRK2 expression (% control) Compound 0.444 1.333 4.000 12.000 IC₅₀ Number μM μM μM μM (μM) 780241 50 107 20 6 n/a* 876015 89 63 46 35 3.8 876039 64 52 30 29 1.3 876043 56 41 20 6 0.7 876091 90 59 30 20 2.1 876092 72 49 33 21 1.5 876093 58 97 31 27 3.1 876187 75 55 47 21 2.2 876235 72 51 28 20 1.4 876380 86 57 41 27 2.6 876639 76 62 42 35 3.0 876668 75 54 31 22 1.7 876732 77 52 44 24 2.2 876741 75 113 46 51 9.0 876852 70 53 38 28 1.8 877171 57 39 32 26 0.7 877395 62 35 22 26 0.7 877396 77 42 32 7 1.2 877587 108 83 48 46 6.7 *IC₅₀ value cannot be calculated

TABLE 68 Dose-dependent reduction of human LRRK2 expression in SH-SY5Y cells LRRK2 expression (% control) Compound 0.444 1.333 4.000 12.000 IC₅₀ Number μM μM μM μM (μM) 780241 52 36 33 11 0.5 876119 80 67 42 22 2.8 876169 64 50 34 26 1.3 876239 71 44 29 23 1.2 876287 55 41 29 23 0.6 876334 64 51 44 37 2.0 876528 83 49 31 19 1.7 876649 78 60 37 32 2.5 876694 66 48 32 26 1.3 876912 68 48 25 30 1.2 876960 52 32 26 8 0.5 877102 67 48 30 32 1.3 877128 66 53 35 30 1.6 877198 73 52 35 17 1.6 877252 75 73 34 31 2.9 877326 50 40 33 12 0.5 877327 78 53 27 25 1.7 877349 47 41 33 24 0.3 877493 88 75 44 37 0.4

TABLE 69 Dose-dependent reduction of human LRRK2 expression in SH-SY5Y cells LRRK2 expression (% control) Compound 0.444 1.333 4.000 12.000 IC₅₀ Number μM μM μM μM (μM) 780241 63 34 25 9 0.8 803643 49 59 54 32 1.7 876049 72 49 46 20 1.8 876074 54 32 28 7 0.5 876100 91 50 32 17 1.9 876124 61 37 17 23 0.7 876146 52 36 30 26 0.4 876170 78 48 41 25 1.9 876173 65 51 23 30 1.2 876244 71 52 29 31 1.6 876482 84 83 48 23 4.0 876553 79 54 32 23 1.8 876748 75 45 25 14 1.2 876821 83 64 40 26 2.8 877204 101 76 45 29 4.1 877305 63 41 28 17 0.9 877307 72 50 31 25 1.5 877496 71 59 34 24 1.9 877617 62 71 31 20 1.8

TABLE 70 Dose-dependent reduction of human LRRK2 expression in SH-SY5Y cells LRRK2 expression (% control) Compound 0.444 1.333 4.000 12.000 IC₅₀ Number μM μM μM μM (μM) 780241 62 39 34 7 0.9 876054 72 74 42 27 3.0 876151 66 62 53 34 3.5 876175 95 48 36 29 2.3 876197 75 64 37 29 2.5 876318 68 58 39 16 1.7 876339 91 77 43 25 3.6 876414 77 52 48 25 2.4 876507 103 80 66 46 9.2 876607 79 57 43 25 2.4 876631 68 43 25 25 1.1 876727 93 79 59 32 5.6 876747 75 54 35 19 1.8 876867 71 54 25 13 1.3 877524 106 106 71 42 9.0 877573 75 59 36 28 2.1 877597 88 79 45 33 4.3 877644 94 67 41 45 4.8 877692 78 67 53 25 3.5

Example 9: Design of Gapmers with Mixed Internucleoside Linkages Complementary to Human LRRK2 RNA

Modified oligonucleotides complementary to a human LRRK2 nucleic acid were designed. The modified oligonucleotides in Table 71 are gapmers. The gapmers have a central gap segment that comprises 2′-deoxynucleosides and is flanked by wing segments on both the 5′ end on the 3′ end comprising and cEt nucleosides and/or 2′-MOE nucleosides. All cytosine residues throughout each gapmer are 5′-methyl cytosines. The internucleoside linkages are mixed phosphodiester internucleoside linkages and phosphorothioate internucleoside linkages. The sequence and chemical notation column specifies the sequence, including 5′-methyl cytosines, sugar chemistry, and the internucleoside linkage chemistry, wherein subscript ‘d’ represents a 2′-deoxyribose sugar; subscript ‘e’ represents a 2′-MOE modified sugar; subscript ‘k’ represents a cEt modified sugar; subscript ‘o’ represents a phosphodiester internucleoside linkage; subscript ‘s’ represents a phosphorothioate internucleoside linkage; and a ‘m’ superscript before the cytosine residue indicates a 5-methyl cytosine. “Start Site” indicates the 5′-most nucleoside to which the gapmer is complementary in the human nucleic acid sequence. “Stop Site” indicates the 3′-most nucleoside to which the gapmer is complementary in the human nucleic acid sequence.

Each modified oligonucleotide listed in the table below is complementary to human LRRK2 nucleic acid sequence SEQ ID NO: 1 or SEQ ID NO: 2, as indicated. ‘N/A’ indicates that the modified oligonucleotide is not complementary to that particular nucleic acid with 100% complementarity.

TABLE 71 Modified oligonucleotides complementary to human LRRK2 RNA SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ Compound Start  Stop Start Stop Sequence and chemistry notation ID Number Site Site Site Site (5’ to 3’) NO 872246 3714 3733 82059 82078 G_(es) ^(m)C_(eo)T_(eo) ^(m)C_(es)A_(es)T_(ds)A_(ds)T_(ds)C_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)  222 A_(ds) ^(m)C_(eo) ^(m)C_(eo)G_(es) ^(m)C_(es)A_(e) 872247 N/A N/A 52154 52173 G_(es) ^(m)C_(eo) ^(m)C_(eo)A_(es)A_(es)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)  599 A_(ds)T_(eo)G_(eo) ^(m)C_(es)A_(es)G_(e) 872248 3494 3513 77243 77262 A_(es)G_(eo)T_(eo)T_(es) ^(m)C_(es) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)  217 ^(m)C_(ds)A_(eo)A_(eo)G_(es)G_(es)G_(e) 872249 7776 7795 145945 145964 G_(es)A_(eo)G_(eo)T_(es)A_(es) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)  398 T_(ds)G_(eo)T_(eo)G_(es)A_(es)A_(e) 872250 988 1007 27963 27982 ^(m)C_(es) ^(m)C_(eo)A_(eo) ^(m)C_(es)A_(es)A_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)  293 G_(ds)A_(ds) ^(m)C_(eo)T_(eo)T_(es) ^(m)C_(es)G_(e) 872251 3714 3733 82059 82078 G_(es) ^(m)C_(eo)T_(es) ^(m)C_(es)A_(es)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)  222 A_(ds) ^(m)C_(eo) ^(m)C_(eo)G_(es) ^(m)C_(es)A_(e) 872252 N/A N/A 52154 52173 G_(es) ^(m)C_(eo) ^(m)C_(es)A_(es)A_(es)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)  599 A_(ds)T_(eo)G_(eo) ^(m)C_(es)A_(es)G_(e) 872253 3494 3513 77243 77262 A_(es)G_(eo)T_(es)T_(es) ^(m)C_(es) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)  217 ^(m)C_(ds)A_(eo)A_(eo)G_(es)G_(es)G_(e) 872254 7776 7795 145945 145964 G_(es)A_(eo)G_(es)T_(es)A_(es) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)  398 A_(ds)T_(ds)G_(eo)T_(eo)G_(es)A_(es)A_(e) 872255 988 1007 27963 27982 ^(m)C_(es)C_(eo)A_(es) ^(m)C_(es)A_(es)A_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)  293 G_(ds)A_(ds) ^(m)C_(eo)T_(eo)T_(es) ^(m)C_(es)G_(e) 872256 3714 3733 82059 82078 G_(es) ^(m)C_(eo)T_(es) ^(m)C_(es)A_(es)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)  222 A_(ds) ^(m)C_(es) ^(m)C_(eo)G_(es) ^(m)C_(es)A_(e) 872257 N/A N/A 52154 52173 G_(es) ^(m)C_(eo) ^(m)C_(es)A_(es)A_(es)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)  599 A_(ds)T_(es)G_(eo) ^(m)C_(es)A_(es)G_(e) 872258 3494 3513 77243 77262 A_(es)G_(eo)T_(es)T_(es) ^(m)C_(es) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)  217 ^(m)C_(ds)A_(es)A_(eo)G_(es)G_(es)G_(e) 872259 7776 7795 145945 145964 G_(es)A_(eo)G_(es)T_(es)A_(es) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)  398 A_(ds)T_(ds)G_(es)T_(eo)G_(es)A_(es)A_(e) 872260 988 1007 27963 27982 ^(m)C_(es) ^(m)C_(eo)A_(es) ^(m)C_(es)A_(es)A_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)sA_(ds)T_(ds)G_(ds)  293 G_(ds)A_(ds) ^(m)C_(es)T_(eo)T_(es) ^(m)C_(es)G_(e) 872261 3714 3733 82059 82078 G_(es) ^(m)C_(es)T_(es) ^(m)C_(es)A_(es)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)  222 A_(ds) ^(m)C_(es) ^(m)C_(eo)G_(es) ^(m)C_(es)A_(e) 872262 N/A N/A 52154 52173 G_(es) ^(m)C_(es) ^(m)C_(es)A_(es)A_(es)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)  599 A_(ds)T_(es)G_(eo) ^(m)C_(es)A_(es)G_(e) 872263 3494 3513 77243 77262 A_(es)G_(es)T_(es)T_(es) ^(m)C_(es) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)  217 ^(m)C_(ds)A_(es)A_(eo)G_(es)G_(es)G_(e) 872264 7776 7795 145945 145964 G_(es)A_(es)G_(es)T_(es)A_(es) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)  398 T_(ds)G_(es)T_(eo)G_(es)A_(es)A_(e) 872265 988 1007 27963 27982 ^(m)C_(es) ^(m)C_(es)A_(es) ^(m)C_(es)A_(es)A_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)  293 A_(ds) ^(m)C_(es)T_(eo)T_(es) ^(m)C_(es)G_(e) 872266 3712 3731 82057 82076 T_(es) ^(m)C_(eo)A_(es)T_(es)A_(es)T_(ds) ^(m)C_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m) 1129 C_(ds)G_(es) ^(m)C_(eo)A_(es)A_(es)G_(e) 872267 3713 3732 82058 82077 ^(m)C_(es)T_(eo) ^(m)C_(es)A_(es)T_(es)A_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)A_(ds) ^(m) 1130 C_(ds) ^(m)C_(es)G_(eo) ^(m)C_(es)A_(es)A_(e) 872268 3715 3734 82060 82079 T_(es) ^(m)G_(eo) ^(m)C_(es)T_(es) ^(m) _(es)A_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(ds)A_(ds)A_(ds) 1131 G_(ds)A_(es) ^(m)C_(eo) ^(m)CsG_(es) ^(m)C_(e) 872269 3716 3735 82061 82080 ^(m)C_(es)T_(eo)G_(es) ^(m)C_(es)T_(es) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(ds)A_(ds) 1132 A_(ds)G_(es)A_(eo) ^(m)C_(es) ^(m)C_(es)G_(e) 872270 3717 3736 82062 82081 G_(es) ^(m)C_(eo)T_(es)G_(es) ^(m)C_(es)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(ds) 1133 A_(ds)A_(es)G_(eo)A_(es) ^(m)C_(es) ^(m)C_(e) 872271 N/A N/A 52151 52170 A_(es)A_(eo)A_(es) ^(m)C_(es)T_(es)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds)Ga_(ds) ^(m) 1677 C_(ds)A_(es)G_(eo)A_(es)A_(es)A_(e) 872272 N/A N/A 52152 52171 ^(m)C_(es)A_(eo)A_(es)A_(es) ^(m)C_(es)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) 1678 G_(ds) ^(m)C_(es)A_(eo)G_(es)A_(es)A_(e) 872273 N/A N/A 52153 52172 ^(m)C_(es) ^(m)C_(eo)A_(es)A_(es)A_(es) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)A_(ds) 1679 T_(ds)G_(es) ^(m)C_(eo)A_(es)G_(es)A_(e) 872274 N/A N/A 52155 52174 T_(es)G_(eo) ^(m)C_(es) ^(m)C_(es)A_(es)A_(ds)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds) 1680 G_(ds)A_(es)T_(eo)G_(es) ^(m)C_(es)A_(e) 872275 N/A N/A 52156 52175 T_(es)T_(eo)G_(es) ^(m)C_(es) ^(m)C_(es)A_(ds)A_(ds)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds) 1681 A_(ds)G_(es)A_(eo)T_(es)G_(es) ^(m)C_(e) 872276 N/A N/A 52157 52176 T_(es)T_(eo)T_(es)G_(es) ^(m)C_(es) ^(m)C_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)A_(ds) 1682 A_(ds)A_(es)G_(eo)A_(es)T_(es)G_(e) 872277 3495 3514 77244 77263 ^(m)C_(es)A_(eo)G_(es)T_(es)T_(es) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ds)T_(ds) ^(m) 1107 C_(ds)T_(ds) ^(m)C_(es)A_(eo)A_(es)G_(es)G_(e) 872278 3496 3515 77245 77264 T_(es) ^(m)C_(eo)A_(es)G_(es)T_(es)T_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ds)T_(ds) 1108 ^(m)C_(ds)T_(es) ^(m)C_(eo)A_(es)A_(es)G_(e) 872279 3497 3516 77246 77265 T_(es)T_(eo) ^(m)C_(es)A_(es)G_(es)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ds) 1109 T_(ds) ^(m)C_(es)T_(eo) ^(m)C_(es)A_(es)A_(e) 872280 7773 7792 145942 145961 T_(es)A_(eo) ^(m)C_(es) ^(m)C_(es) ^(m)C_(es)T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)T_(ds) 1432 G_(ds)A_(es)A_(eo) ^(m)C_(es)A_(es)T_(e) 872281 7774 7793 145943 145962 G_(es)T_(eo)A_(es) ^(m)C_(es) ^(m)C_(es) ^(m)C_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds) 1433 T_(ds)G_(es)A_(eo)A_(es) ^(m)C_(es)A_(e) 872282 7775 7794 145944 145963 A_(es)G_(eo)T_(es)A_(es) ^(m)C_(es) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds) 1434 G_(ds)T_(es)G_(eo)A_(es)A_(es) ^(m)C_(e) 872283 7777 7796 145946 145965 T_(es)G_(eo)A_(es)G_(es)T_(es)A_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) 1435 A_(ds)T_(es)G_(eo)T_(es)G_(es)A_(e) 872284 7778 7797 145947 145966 G_(es)T_(eo)G_(es)A_(es)G_(es)T_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds) 1436 ^(m)C_(ds)A_(es)T_(eo)G_(es)T_(es)G_(e) 872285 7779 7798 145948 145967 T_(es)G_(eo)T_(es)G_(es)A_(es)G_(ds)T_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds) ^(m) 1437 C_(ds) ^(m)C_(es)A_(eo)T_(es)G_(es)T_(e) 874144 N/A N/A 82056 82075 ^(m)C_(es)A_(eo)T_(eo)A_(eo)T_(es) ^(m)C_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds) 3820 G_(ds) ^(m)C_(eo)A_(eo)A_(es)G_(es) ^(m)G 874145 3493 3512 77242 77261 G_(es)T_(eo)T_(eo) ^(m)C_(eo) ^(m)C_(es)T_(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) 3821 A_(ds)A_(eo)G_(eo)G_(es)G_(es)G_(e) 874146 3492 3511 77241 77260 T_(es)T_(eo) ^(m)C_(es) ^(m)C_(es)T_(es)T_(ds) ^(m)C_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) 3822 A_(ds)A_(ds)G_(es)G_(eo)G_(es)G_(es)G_(e) 874147 3491 3510 77240 77259 T_(es)C_(eo) ^(m)C_(eo)T_(eo)T_(es) ^(m)C_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)A_(ds) 3823 G_(ds)G_(eo)G_(eo)G_(es)G_(es)A_(e) 874148 4117 4136 86612 86631 T_(es) ^(m)C_(eo)A_(eo)T_(eo)A_(es)A_(ds)G_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ds) ^(m) 3824 C_(ds)G_(eo)G_(eo)T_(es)T_(es)A_(e) 874149 N/A N/A 82056 82075 ^(m)C_(es)A_(eo)T_(es)A_(es)T_(es) ^(m)C_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds) 3820 G_(ds) ^(m)C_(es)A_(eo)A_(es)G_(es) ^(m)C_(e) 874150 3493 3512 77242 77261 G_(es)T_(eo)T_(eo) ^(m)C_(eo) ^(m)C_(es)T_(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) 3821 A_(ds)A_(eo)G_(eo)G_(es)G_(es)G_(e) 874151 3492 3511 77241 77260 T_(es)T_(eo) ^(m)C_(es) ^(m)C_(es)T_(es)T_(ds) ^(m)C_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) 3822 A_(ds)A_(ds)G_(es)G_(eo)G_(es)G_(es)G_(e) 890206 N/A N/A 61977 61996 ^(m)C_(es)T_(eo)T_(eo)T_(eo) ^(m)C_(es)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ds) ^(m) 3825 C_(ds)T_(ds)A_(eo)T_(eo)T_(es)A_(es)A_(e) 890207 N/A N/A 61978 61997 T_(es) ^(m)C_(eo)T_(eo)T_(eo)T_(es) ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ds) 3826 ^(m)C_(ds)T_(eo)A_(eo)T_(es)T_(es)A_(e) 890208 N/A N/A 61979 61998 ^(m)C_(es)T_(eo) ^(m)C_(eo)T_(eo)T_(es)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds) 3827 ^(m)C_(ds) ^(m)C_(eo)T_(eo)A_(es)T_(es)T_(e) 890209 N/A N/A 61980 61999 T_(es) ^(m)C_(eo)T_(eo) ^(m)C_(eo)T_(es)T_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) 3828 A_(ds) ^(m)C_(eo) ^(m)C_(eo)T_(es)A_(es)T_(e) 934514 879 898 21710 21729 t_(es)G_(eo) ^(m)C_(es)T_(es)T_(es)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ds)T_(ds) ^(m)  862 C_(ds) ^(m)C_(es)A_(eo) ^(m)C_(es) ^(m)C_(es)A_(e) 934515 880 899 21711 21730 A_(es)T_(eo)G_(es) ^(m)C_(es)T_(es)T_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ds)T_(ds)  863 ^(m)C_(es) ^(m)C_(eo)A_(eo) ^(m)C_(es) ^(m)C_(e) 934516 837 856 21668 21687 G_(es) ^(m)C_(eo) ^(m)C_(es)A_(es) ^(m)C_(es)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)A_(ds) 2833 ^(m)C_(ds)T_(es)T_(eo) ^(m)C_(es) ^(m)C_(es)A_(e) 934517 840 859 21671 21690 A_(es)T_(eo)T_(es)G_(es) ^(m)C_(es) ^(m)C_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)A_(ds) 3362 G_(ds)G_(es)A_(eo) ^(m)C_(es)T_(es)T_(e) 934517 840 859 21671 21690 A_(es)T_(eo)T_(es)G_(es) ^(m)C_(es) ^(m)C_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)A_(ds) 3362 G_(ds)G_(es)A_(eo) ^(m)C_(es)T_(es)T_(e) 934518 846 865 21677 21696 ^(m)C_(es) ^(m)C_(eo)T_(es)G_(es)A_(es) ^(m)C_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m) 3514 C_(ds)T_(ds) ^(m)C_(es)A_(eo)T_(es)G_(es)A_(e) 934518 846 865 21677 21696 ^(m)C_(es) ^(m)C_(eo)T_(es)G_(es)A_(es) ^(m)C_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m) 3514 C_(ds)T_(ds) ^(m)C_(es)A_(eo)T_(es)G_(es)A_(e) 934519 N/A N/A 23873 23892 T_(es)G_(eo) ^(m)C_(es)A_(es)T_(es)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)A_(ds)T_(ds)G_(ds)A_(ds) 2706 A_(es)A_(eo)A_(es) ^(m)C_(es)A_(e) 934520 1233 1252 29584 29603 G_(es)A_(eo)G_(es)A_(es)T_(es)T_(ds)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)T_(ds)G_(ds) ^(m)C_(ds) 3287 ^(m)C_(es) ^(m)C_(eo)a_(es)G_(es) ^(m)C_(e) 934521 1426 1445 35373 35392 G_(es)T_(eo)A_(es)T_(es)T_(es) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds)A_(ds)T_(ds)A_(ds)  917 A_(es) ^(m)C_(eo)A_(es)G_(es)T_(e) 934522 1435 1454 35382 35401 ^(m)C_(es)A_(eo)T_(es)T_(es) ^(m)C_(es)A_(ds)G_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)Ta_(ds) ^(m)  918 C_(ds) ^(m)C_(es)T_(eo)T_(es)T_(es)T_(e) 934523 1488 1507 35435 35454 G_(es) ^(m)C_(eo) ^(m)C_(es)A_(es) ^(m)C_(es)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds)  922 A_(ds) ^(m)C_(ds)T_(es)T_(eo) ^(m)C_(es)A_(es)G_(e) 934524 1700 1719 41933 41952 A_(es) ^(m)C_(eo) ^(m)C_(es)A_(es)T_(es)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ds)T_(ds) 3670 A_(ds)T_(es)G_(eo)A_(es)T_(es)G_(e) 934525 1701 1720 41934 41953 A_(es)A_(eo) ^(m)C_(es) ^(m)C_(es)A_(es)T_(ds)A_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ds) 3365 T_(ds)A_(es)T_(eo)G_(es)A_(es)T_(e) 934526 N/A N/A 48094 48113 T_(es)G_(eo) ^(m)C_(es)A_(es)T_(es)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ds)A_(ds)G_(ds)G_(ds) 2260 T_(es)A_(eo)G_(es)T_(es)A_(e) 934528 2267 2286 56275 56294 ^(m)C_(es)T_(eo)G_(es)T_(es)T_(es)A_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds)A_(ds)T_(ds) ^(m)C_(ds) 2685 A_(ds) ^(m)C_(es)A_(eo) ^(m)C_(es)G_(es) ^(m)C_(e) 934529 2452 2471 62073 62092 T_(es)G_(eo)T_(es) ^(m)C_(es)A_(es) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds) 3366 A_(ds)A_(ds)T_(es)G_(eo) ^(m)C_(es)T_(es)T_(e) 934530 2453 2472 62074 62093 ^(m)C_(es)T_(eo)G_(es)T_(es) ^(m)C_(es)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m) 3443 C_(ds)A_(ds)A_(es)T_(eo)G_(es) ^(m)C_(es)T_(e) 934531 2454 2473 62075 62094 G_(es) ^(m)C_(eo)T_(es)G_(es)T_(es) ^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m) 3518 C_(ds) ^(m)C_(ds)A_(es)A_(eo)T_(es)G_(es) ^(m)C_(e) 934532 2456 2475 62077 62096 T_(es)G_(eo)G_(es) ^(m)C_(es)T_(e)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds) 3595 ^(m)C_(ds) ^(m)C_(es) ^(m)C_(eo)A_(es)A_(es)T_(e) 934533 2363 2382 61984 62003 ^(m)C_(es)T_(eo)G_(es) ^(m)C_(es)T_(es) ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)  258 C_(ds)A_(ds) ^(m)C_(es)A_(eo)T_(es)A_(es) ^(m)C 934534 2871 2890 71714 71733 ^(m)C_(es)T_(eo)G_(es)T_(es)A_(es)A_(ds)T_(ds)A_(ds) ^(m)C_(ds)G_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m) 3140 C_(ds)T_(es) ^(m)C_(eo)G_(es)G_(es)T_(e) 934535 N/A N/A 73941 73960 ^(m)C_(es)A_(eo)G_(es)A_(es)T_(es) ^(m)C_(ds)T_(ds)G_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) 3636 T_(ds)T_(es)G_(eo) ^(m)C_(es) ^(m)C_(es)T_(e) 934536 3582 3601 77331 77350 G_(es)G_(eo) ^(m)C_(es)A_(es) ^(m)C_(es)T_(ds)G_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ds)  219 ^(m)C_(ds) ^(m)C_(es)A_(eo) ^(m)C_(es)T_(es)T_(e) 934537 3850 3869 82195 82214 G_(es)T_(eo)T_(es)T_(es) ^(m)C_(es)T_(ds) ^(m)C_(ds)T_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(ds) 3369 G_(ds)A_(es) ^(m)C_(eo) ^(m)C_(es)A_(es)T_(e) 934538 3852 3871 82197 82216 ^(m)C_(es)A_(eo)G_(es)T_(es)T_(es)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) 3446 T_(ds)A_(es)G_(eo)A_(es) ^(m)C_(es) ^(m)C_(e) 934540 N/A N/A 91040 91059 A_(es)T_(eo)G_(es)T_(es)A_(es)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds) ^(m) 1828 C_(ds) ^(m)C_(es)A_(eo)G_(es)A_(es)G_(e) 934541 N/A N/A 91041 91060 ^(m)C_(es)A_(eo)T_(es)G_(es)T_(es)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)A_(ds)A_(ds) ^(m) 1829 C_(ds) ^(m)C_(es) ^(m)C_(eo)A_(es)G_(es)A_(e) 934542 N/A N/A 91046 91065 g_(es)T_(eo)T_(es)T_(es)T_(es) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m) 1833 C_(ds)T_(es)T_(eo)A_(es)A_(es) ^(m)C_(e) 934543 N/A N/A 91047 91066 T_(es)G_(eo)T_(es)T_(es)T_(es)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) 1834 ^(m)C_(es)T_(eo)T_(es)A_(es)A_(e) 934544 N/A N/A 91048 91067 ^(m)C_(es)T_(eo)G_(es)T_(es)T_(es)T_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)T_(ds) ^(m) 1835 C_(ds)T_(es) ^(m)C_(eo)T_(es)T_(es)A_(e) 934545 4727 4746 92150 92169 G_(es)G_(eo) ^(m)C_(es)A_(es) ^(m)C_(es)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ds)G_(ds) ^(m) 2690 C_(ds)T_(es) ^(m)C_(eo) ^(m)C_(es)G_(es)A_(e) 934546 5073 5092 98221 98240 ^(m)C_(es)T_(eo)G_(es)G_(es)A_(es)A_(ds)T_(ds)T_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(ds)G_(ds) 3524 G_(es)A_(eo)G_(es) ^(m)C_(es)T_(e) 934547 N/A N/A 91042 91061 T_(es) ^(m)C_(eo)A_(es)T_(es)G_(es)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds)C_(ds)T_(ds)T_(ds)A_(ds) 1830 A_(ds) ^(m)C_(es) ^(m)C_(eo) ^(m)C_(es)A_(es)G_(e) 934548 541 560 13807 13826 T_(es)A_(eo) ^(m)C_(es) ^(m)C_(es)T_(es)G_(ds)A_(ds)A_(ds)G_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)  828 A_(ds)G_(es)G_(eo)A_(es)G_(es)A_(e) 934549 540 559 13806 13825 A_(es) ^(m)C_(eo) ^(m)C_(es)T_(es)G_(es)A_(ds)A_(ds)G_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)A_(ds)  827 G_(ds)G_(es)A_(eo)G_(es)A_(es)T_(e) 934552 734 753 18633 18652 G_(es) ^(m)C_(eo)A_(eS) ^(m)C_(es)T_(eS)T_(ds)A_(ds)A_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds) ^(m) 3513 C_(ds)A_(es)T_(eo)A_(es)T_(es)A_(e) 934553 737 756 18636 18655 A_(es)A_(eo) ^(m)C_(es)G_(es) ^(m)C_(es)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds)A_(ds)A_(ds) 1997 T_(ds)A_(es)T_(eo) ^(m)C_(es)A_(es)T_(e) 934554 738 757 18637 18656 T_(es)A_(eo)A_(es) ^(m)C_(es)G_(es) ^(m)C_(ds)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds)A_(ds) 2073 A_(ds)T_(es)A_(eo)T_(es) ^(m)C_(es)A_(e) 934555 740 759 18639 18658 G_(es)T_(eo)T_(es)A_(es)A_(es) ^(m)C_(ds)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)A_(ds)A_(ds) ^(m) 2148 C_(ds)A_(es)A_(eo)T_(es)A_(es)T_(e) 934556 735 754 18634 18653 ^(m)C_(es)G_(eo) ^(m)C_(es)A_(es) ^(m)C_(es)T_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)A_(ds)  852 T_(ds) ^(m)C_(es)A_(eo)T_(es)A_(es)T_(e) 934557 736 755 18635 18654 A_(es) ^(m)C_(eo)G_(es) ^(m)C_(es)A_(es) ^(m)C_(ds)T_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds) 3590 A_(ds)T_(es) ^(m)C_(eo)A_(es)T_(es)A_(e) 934558 N/A N/A 19521 19540 A_(es)G_(eo) ^(m)C_(es)A_(es)A_(es)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds)A_(ds) 3385 G_(ds) ^(m)C_(es)A_(eo)T_(es)A_(es) ^(m)C_(e) 934584 7772 7791 145941 145960 A_(es) ^(m)C_(eo) ^(m)C_(es) ^(m)C_(es)T_(es)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)T_(ds) 1431 G_(ds)A_(ds)A_(es) ^(m)C_(eo)A_(es)T_(es)T_(e) 934585 7780 7799 145949 145968 A_(es)T_(eo)G_(es)T_(es)G_(es)A_(ds)G_(ds)T_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds) 1438 T_(ds) ^(m)C_(es) ^(m)C_(eo)A_(es)T_(es)G_(e) 934586 732 751 18631 18650 A_(es) ^(m)C_(eo)T_(es)T_(es)A_(es)A_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)A_(ds) 3361 T_(ds)A_(es)T_(eo)A_(es)A_(es)T_(e) 934587 733 752 18632 18651 ^(m)C_(es)A_(eo) ^(m)C_(es)T_(es)T_(es)A_(ds)A_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds) 3438 A_(ds)T_(es)A_(eo)T_(es)A_(es)A_(e) 934588 2451 2470 62072 62091 G_(es)T_(eo) ^(m)C_(es)A_(es) ^(m)C_(es) ^(m)C_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)  188 A_(ds)T_(ds)G_(es) ^(m)C_(eo)T_(es)T_(es)A_(e) 934589 835 854 21666 21685 ^(m)C_(es)A_(eo) ^(m)C_(es)T_(es) ^(m)C_(es)A_(ds)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds)  860 T_(ds) ^(m)C_(es) ^(m)C_(eo)A_(es) ^(m)C_(es)A_(e) 934590 836 855 21667 21686 ^(m)C_(es) ^(m)C_(eo)A_(es) ^(m)C_(es)T_(es) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)A_(ds) ^(m) 2757 C_(ds)T_(ds)T_(es) ^(m)C_(eo) ^(m)C_(es)A_(es)C_(e) 934591 834 853 21665 21684 A_(es) ^(m)C_(eo)T_(es) ^(m)C_(es)A_(es)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds)T_(ds) ^(m) 3286 C_(ds) ^(m)C_(es)A_(eo) ^(m)C_(es)A_(es)T_(e) 934592 2362 2381 61983 62002 T_(es)G_(eo) ^(m)C_(es)T_(es) ^(m)C_(es)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)  257 ^(m)C_(ds)A_(es)T_(eo)A_(es) ^(m)C_(es) ^(m)C_(e) 934593 896 915 21727 21746 ^(m)C_(es)T_(eo)T_(es)T_(es) ^(m)C_(es)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)G_(ds)G_(ds)  291 G_(ds)A_(es)A_(eo)T_(es)G_(es) ^(m)C_(e) 934594 2365 2384 61986 62005 G_(es)A_(eo) ^(m)C_(es)T_(es)G_(es) ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds) 1017 T_(ds) ^(m)C_(es)A_(eo) ^(m)C_(es)A_(es)T_(e) 934595 2364 2383 61985 62004 A_(es) ^(m)C_(eo)T_(es)G_(es) ^(m)C_(es)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)  259 ^(m)C_(ds)A_(es) ^(m)C_(eo)A_(es)T_(es)A_(e) 934596 542 561 13808 13827 T_(es)T_(eo)A_(es) ^(m)C_(es) ^(m)C_(es)T_(ds)G_(ds)A_(ds)A_(ds)G_(ds)T_(ds)T_(ds)A_(ds)G_(ds)G_(ds)  829 A_(es)G_(eo)G_(es)A_(es)G_(e) 934597 4112 4131 86607 86626 A_(es)G_(eo)T_(eS)T_(eS)T_(es) ^(m)C_(ds)A_(ds)T_(ds)T_(ds) ^(m)C_(ds)G_(ds)G_(ds)T_(ds)T_(ds)A_(ds) 1172 T_(es)A_(eo)A_(es)G_(es)G_(e) 934599 2368 2387 61989 62008 T_(es)G_(eo)G_(es)G_(es)A_(es) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ds)  185 T_(ds)T_(es) ^(m)C_(eo)T_(es) ^(m)C_(es)A_(e) 934600 2369 2388 61990 62009 T_(es)T_(eo)G_(es)G_(es)G_(es)A_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) 1019 T_(ds)T_(es)T_(eo) ^(m)C_(es)T_(es) ^(m)C_(e) 952334 607 626 16127 16146 A_(es)G_(eo)T_(es)G_(es) ^(m)C_(es)A_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)A_(ds)  839 A_(ds)A_(es)A_(eo)A_(es)T_(es)T_(e) 952335 730 749 18629 18648 T_(es)T_(eo)A_(es)A_(es) ^(m)C_(es)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 3666 A_(es)A_(eo)T_(es) ^(m)C_(es)T_(e) 952336 872 891 21703 21722 A_(es)T_(eo)A_(es)G_(es) ^(m)C_(es)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m) 1998 C_(ds)A_(ds)A_(es)T_(eo)A_(es)T_(es)T_(e) 952338 875 894 21706 21725 T_(es)T_(eo) ^(m)C_(es)A_(es)T_(es)A_(ds)G_(ds) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) 2149 C_(ds) ^(m)C_(ds)A_(es) ^(m)C_(eo)A_(es)A_(es)T_(e) 952340 877 896 21708 21727 ^(m)C_(es)T_(eo)T_(es)T_(es) ^(m)C_(es)A_(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) 2986 A_(ds) ^(m)C_(es) ^(m)C_(eo)A_(es) ^(m)C_(es)A_(e) 952358 3227 3246 76361 76380 A_(es)A_(eo)G_(es)T_(es) ^(m)C_(es) ^(m)C_(ds)A_(ds)A_(ds)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds)T_(ds) ^(m) 2534 C_(ds)A_(es)A_(eo)A_(es) ^(m)C_(es)T_(e) 952359 3228 3247 76362 76381 ^(m)C_(es)A_(eo)A_(es)G_(es)T_(es) ^(m)C_(ds) ^(m)C_(ds)A_(ds)A_(ds)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds) 2610 T_(ds) ^(m)C_(es)A_(eo)A_(es)A_(es) ^(m)C_(e) 952360 3229 3248 76363 76382 G_(es) ^(m)C_(eo)A_(es)A_(es)G_(es)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)A_(ds)A_(ds)T_(ds)G_(ds)T_(ds) 2687 G_(ds)T_(es) ^(m)C_(eo)A_(es)A_(es)A_(e) 952361 3231 3250 76365 76384 G_(es)T_(eo)G_(es) ^(m)C_(es)A_(es)A_(ds)G_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)A_(ds)A_(ds)T_(ds) 3141 G_(ds)T_(es)G_(eo)T_(es) ^(m)C_(es)A_(e) 952362 3498 3517 77247 77266 ^(m)C_(es)T_(eo)T_(es) ^(m)C_(es)A_(es)G_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ds) 1110 G_(ds)T_(es) ^(m)C_(eo)T_(es) ^(m)C_(es)A_(e) 952363 3499 3518 77248 77267 T_(es) ^(m)C_(eo)T_(es)T_(es) ^(m)C_(es)A_(ds)G_(ds)T_(ds)T_(ds) ^(m)C_(ds)C_(ds)T_(ds)T_(ds) ^(m)C_(ds) 1111 A_(ds)G_(es)T_(eo) ^(m)C_(es)T_(es) ^(m)C_(e) 952364 3505 3524 77254 77273 T_(es)T_(eo)A_(es)A_(es)A_(es)A_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ds)T_(ds)T_(ds) 1112 ^(m)C_(es) ^(m)C_(eo)T_(es)T_(es) ^(m)C_(e) 952365 3718 3737 82063 82082 T_(es)G_(eo) ^(m)C_(es)T_(es)G_(es) ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) 1134 A_(ds)A_(es)A_(eo)G_(es)A_(es) ^(m)C_(e) 952366 3719 3738 82064 82083 t_(es)T_(eo)G_(es) ^(m)C_(es)T_(es)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds) 1135 T_(ds)A_(es)A_(eo)A_(es)G_(es)A_(e) 952367 3723 3742 82068 82087 A_(es)T_(eo) ^(m)C_(es)A_(es)T_(es)T_(ds)G_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds) 1136 T_(ds)A_(es)T_(eo) ^(m)C_(es)T_(es)A_(e) 952368 4106 4125 86601 86620 A_(es)T_(eo)T_(es) ^(m)C_(es)G_(es)G_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)C_(ds) 1167 A_(es) ^(m)C_(eo)A_(es)G_(es) ^(m)C_(e) 952369 4107 4126 86602 86621 ^(m)C_(es)A_(eo)T_(es)T_(es) ^(m)C_(es)G_(ds)G_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds) 1168 ^(m)C_(es)A_(eo) ^(m)C_(es)A_(es)G_(e) 952370 4108 4127 86603 86622 T_(es) ^(m)C_(eo)A_(es)T_(es)T_(es) ^(m)C_(ds)G_(ds)G_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds)G_(ds) 1169 G_(es) ^(m)C_(eo)A_(es) ^(m)C_(es)A_(e) 952371 4109 4128 86604 86623 T_(es)T_(eo) ^(m)C_(es)A_(es)T_(es)T_(ds) ^(m)C_(ds)G_(ds)G_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) 1170 G_(es)G_(eo) ^(m)C_(es)A_(es) ^(m)C_(e) 952372 4110 4129 86605 86624 T_(es)T_(eo)T_(es) ^(m)C_(es)A_(es)T_(ds)T_(ds) ^(m)C_(ds)G_(ds)G_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds) 1171 A_(es)G_(eo)G_(es) ^(m)C_(es)A_(e) 952373 4111 4130 86606 86625 G_(es)T_(eo)T_(es)T_(es) ^(m)C_(es)A_(ds)T_(ds)T_(ds) ^(m)C_(ds)G_(ds)G_(ds)T_(ds)T_(ds)A_(ds)T_(ds)  235 A_(es)A_(eo)G_(es)G_(es) ^(m)C_(e) 952374 4115 4134 86610 86629 A_(es)T_(eo)A_(es)A_(es)G_(es)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ds) ^(m)C_(ds)G_(ds)G_(ds) 1175 T_(es)T_(eo)A_(es)T_(es)A_(e) 952375 608 627 16128 16147 G_(es)A_(eo)G_(es)T_(es)G_(es) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)  279 A_(ds)A_(es)A_(eo)A_(es)A_(es)T_(e) 952376 609 628 16129 16148 T_(es)G_(eo)A_(es)G_(es)T_(es)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)  840 C_(ds)A_(es)A_(eo)A_(es)A_(es)A_(e) 952377 610 629 16130 16149 A_(es)T_(eo)G_(eS)A_(es)G_(eS)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)  841 ^(m)C_(es)A_(eo)A_(es)A_(es)A_(e) 952378 611 630 16131 16150 A_(es)A_(eo)T_(es)G_(es)A_(es)G_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds)  280 A_(ds)T_(es) ^(m)C_(eo)A_(es)A_(es)A_(e) 952379 612 631 16132 16151 A_(es)A_(eo)A_(es)T_(es)G_(es)A_(ds)G_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds) ^(m)  842 C_(ds)A_(es)T_(eo) ^(m)C_(es)A_(es)A_(e) 952380 613 632 16133 16152 G_(es)A_(eo)A_(es)A_(es)T_(es)G_(ds)A_(ds)G_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)  843 ^(m)C_(es)A_(eo)T_(es) ^(m)C_(es)A_(e) 952381 620 639 16140 16159 T_(es)T_(eo)G_(es)G_(es) ^(m)C_(es)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds)G_(ds)A_(ds)G_(ds)  844 T_(es)G_(eo) ^(m)C_(es)A_(es)T_(e) 953599 732 748 18631 18647 T_(es)A_(eo)A_(eo) ^(m)C_(es)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)Tk_(o) 3829 A_(es)A_(es)T_(e) 953600 733 749 18632 18648 T_(es)T_(eo)A_(eo)A_(es) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)Ak_(o) 3830 T_(es)A_(es)A_(e) 953601 734 750 18633 18649 ^(m)C_(es)T_(eo)T_(eo)A_(es)A_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)A_(ds)TK_(o) 3831 A_(es)T_(es)A_(e) 953602 735 751 18634 18650 A_(es) ^(m)C_(eo)T_(eo)T_(es)A_(ds)A_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)Ak_(o) 3832 T_(es)A_(e)T_(e) 953603 736 752 18635 18651 ^(m)C_(es)A_(eo) ^(m)C_(eo)T_(es)T_(ds)A_(ds)A_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds) ^(m)Ck_(o) 3833 A_(es)T_(es)A_(e) 953604 1874 1890 52788 52804 A_(es)G_(eo) ^(m)C_(eo)A_(es) ^(m)C_(ds)T_(ds)G_(ds)A_(ds)A_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)Tk_(o) 3834 A_(es)G_(es) ^(m)C_(e) 953605 1791 1807 52705 52721 A_(es) ^(m)C_(eo)A_(eo)T_(es)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds)A_(ds)A_(ds)T_(ds) ^(m)C_(ds) ^(m)Ck_(o) 3835 ^(m)C_(es)A_(es)G_(e) 953606 3493 3509 77242 77258 ^(m)C_(es) ^(m)C_(eo)T_(eo)T_(es) ^(m)C_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)A_(ds) 3836 Gk_(o)G_(es)G_(es)G_(e) 953607 3713 3729 82058 82074 A_(es)T_(eo)A_(eo)T_(es) ^(m)C_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)Gk_(o) 3837 ^(m)C_(es)A_(es)A_(e) 953608 987 1003 27962 27978 A_(es)A_(eo)A_(eo) ^(m)C_(es)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds)Tk_(o) 3838 ^(m)C_(es)G_(es)T_(e) 953609 4110 4126 86605 86621 ^(m)C_(es)A_(eo)T_(eo)T_(es) ^(m)C_(ds)G_(ds)G_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds)Gk_(o) 3839 G_(es)C_(es)A_(e) 953610 7775 7791 145944 145960 A_(es) ^(m)C_(eo) ^(m)C_(eo) ^(m)C_(es)T_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)T_(ds) 3840 Gk_(o)A_(es)A_(es) ^(m)C_(e) 953611 879 895 21710 21726 T_(es)T_(eo)T_(eo) ^(m)C_(es)A_(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)Ak_(o) 3841 ^(m)C_(es) ^(m)C_(es)A_(e) 953612 834 850 21665 21681 ^(m)C_(es)A_(eo)T_(eo)G_(es)A_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) 3842 Ak_(o) ^(m)C_(es)A_(es)T_(e) 953613 606 622 16126 16142 ^(m)C_(es)A_(eo)T_(eo)G_(es)G_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)A_(ds)A_(ds)A_(ds)A_(ds)Ak_(o) 3843 T_(es)T_(es)A_(e) 953614 990 1006 27965 27981 ^(m)C_(es)A_(eo) ^(m)C_(eo)A_(es)A_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds) 3844 Ak_(o) ^(m)C_(es)T_(es)T_(e) 953615 3497 3513 77246 77262 A_(es)G_(eo)T_(eo)T_(es) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)Tk_(o) 3845 ^(m)C_(es)A_(es)A_(e) 953616 4108 4124 86603 86619 T_(es)T_(eo) ^(m)C_(eo)G_(es)G_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)Ck_(o) 3846 A_(es)C_(es)A_(e) 953617 1698 1714 41931 41947 A_(es)T_(eo)T_(eo)T_(es)A_(ds)G_(ds) ^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)G_(ds)A_(ds)Tk_(o)G_(es) 3847 A_(es)A_(e)

Example 10: Effect of 5-10-5 MOE Gapmers with Mixed Internucleoside Linkages on Human LRRK2 RNA Expression In Vitro Via Free Uptake

Modified oligonucleotides selected from the examples above were tested at various doses in A431 cells by free uptake. Cells were plated at a density of 10,000 cells per well with 0.039, 0.156, 0.625, 2.500 and 10.000 μM concentrations of modified oligonucleotide, as specified in the tables below. After a treatment period of approximately 24 hours, total RNA was isolated from the cells and LRRK2 RNA levels were measured by quantitative real-time PCR. Human LRRK2 primer probe set RTS3132 (described herein in Example 2) was used to measure RNA levels. LRRK2 RNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented in the table below as percent LRRK2 RNA levels relative to untreated control cells. As illustrated in the tables below, LRRK2 RNA levels were reduced in a dose-dependent manner in modified oligonucleotide-treated cells. IC50 was calculated using the “log(inhibitor) vs. response—variable slope (4 parameters)” formula using Prism6 software.

TABLE 72 Dose-dependent reduction of human LRRK2 expression in A431 cells by free uptake LRRK2 expression (% control) Compound 0.039 0.156 0.625 2.500 10.000 IC₅₀ Number μM μM μM μM μM (μM) 780160 101 86 56 55 48 4.5 780161 102 85 58 31 45 1.9 780164 95 75 63 52 40 3.1 780166 94 42 42 31 32 0.4 780241 70 70 46 35 50 1.3 802655 81 76 58 52 36 2.3 802665 78 73 62 59 53 14.3 802678 77 44 28 24 26 0.2 802714 84 84 64 47 40 2.8 802758 84 51 25 23 29 0.2 802770 74 68 44 28 31 0.5 802784 88 70 37 20 25 0.5 802938 109 53 50 38 34 1.0 802939 96 80 63 44 31 1.9 802963 92 102 88 78 64 26.0 803000 85 84 60 30 33 1.3 803006 89 77 53 43 37 1.7 803268 90 93 55 46 27 1.7 803270 86 80 52 44 43 2.2 872255 96 67 36 29 22 0.5 872260 52 55 33 23 29 0.1 876031 96 60 33 21 20 0.4 876180 101 94 90 90 80 >300 876190 81 68 36 24 23 0.4 876604 91 71 46 28 41 0.0 934517 80 86 43 38 48 0.9 934518 82 54 28 25 31 1.8 934523 71 49 30 15 23 0.3 934528 71 57 50 26 34 0.2 934529 76 43 24 27 29 0.4 934530 89 68 40 28 25 0.2 934553 99 73 51 33 31 0.6 934554 95 73 72 40 35 1.0 934556 63 59 41 26 28 2.1 934557 107 63 51 33 33 0.3

Example 11: Effect of Modified Oligonucleotides on Rhesus Monkey LRRK2 RNA In Vitro, Multiple Doses

Modified oligonucleotides selected from the examples above, which are also complementary to rhesus monkey LRRK2 were tested at various doses in LLC-MK2 monkey cells. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 0.011, 0.034, 0.103, 0.309, 0.926, 2.778, 8.333, and 25.000 μM concentrations of modified oligonucleotide, as specified in the tables below. Also tested were control oligonucleotides, 676630, a 5-10-5 MOE gapmer with mixed phosphodiester and phosphorothioate backbone with no known target and the sequence CCTATAGGACTATCCAGGAA (SEQ ID NO: 3848). After a treatment period of approximately 24 hours, total RNA was isolated from the cells and LRRK2 RNA levels were measured by quantitative real-time PCR. Human LRRK2 primer probe set hLRRK2 LTS35700 (forward sequence CCAGGTACAATGCAAAGCTTAAT, designated herein as SEQ ID NO: 20; reverse sequence TCAGTCCAATCACTGACAAGTT, designated herein as SEQ ID NO: 21; probe sequence TTGGGAAGTCCTTGGTGTTCACCA, designated herein as SEQ ID NO: 22) was used to measure RNA levels. LRRK2 RNA levels were adjusted according to total RNA content, as measured by RIBOGREEN Results are presented in the table below as percent LRRK2 RNA levels relative to untreated control cells. As illustrated in the tables below, LRRK2 RNA levels were reduced in a dose-dependent manner in modified oligonucleotide-treated cells. IC50 was calculated using the “log(inhibitor) vs. response—variable slope (4 parameters)” formula using Prism6 software.

TABLE 73 Dose-dependent reduction of human LRRK2 expression in LLC-MK2 rhesus monkey cells LRRK2 expression (% control) Compound 0.011 0.034 0.103 0.309 0.926 2.778 8.333 25.000 IC₅₀ Number μM μM μM μM μM μM μM μM (μM) 676630 118 114 124 128 123 134 125 125 n/a# 780241 114 118 116 92 67 51 46 41 6.4  802714** 122 116 130 131 112 80 41 20 7.4  803268* 101 109 105 112 108 89 76 69 50.4  876031 122 113 106 84 46 14 8 1 0.9  876604** 97 95 99 97 107 107 105 77 n/a# 934556 88 84 71 55 30 12 11 6 0.3 #IC₅₀ value cannot be calculated *This modified oligonucleotide is complementary to and contains one mismatch to rhesus monkey LRRK2 nucleic acid SEQ ID NO: 3 **These modified oligonucleotides are complementary to and contain two mismatches to rhesus monkey LRRK2 nucleic acid SEQ ID NO: 3

Example 12: Effect of Modified Oligonucleotides on Human LRRK2 RNA Expression In Vitro, Multiple Doses

Modified oligonucleotides described above were tested at various doses in SH-SY5Y cells. Cells were plated at a density of 20,000 cells per well and transfected using electroporation with 0.011, 0.034, 0.103, 0.309, 0.926, 2.778, 8.333, and 25.000 μM of modified oligonucleotide, as specified in the tables below. Also tested was control oligonucleotide, 676630, a 5-10-5 MOE gapmer with mixed phosphodiester and phosphorothioate backbone with no known target. After a treatment period of approximately 24 hours, total RNA was isolated from the cells and LRRK2 RNA levels were measured by quantitative real-time PCR. Human LRRK2 primer probe set LTS35700 (described herein in Example 11) was used to measure RNA levels. LRRK2 RNA levels were adjusted according to total RNA content, as measured by RIBOGREEN Results are presented in the table below as percent LRRK2 RNA levels relative to untreated control cells. As illustrated in the tables below, LRRK2 RNA levels were reduced in a dose-dependent manner in modified oligonucleotide-treated cells. IC50 was calculated using the “log(inhibitor) vs. response—variable slope (4 parameters)” formula using Prism6 software.

TABLE 74 Dose-dependent reduction of human LRRK2 expression in SH-SY5Y Cells LRRK2 expression (% control) Compound 0.011 0.034 0.103 0.309 0.926 2.778 8.333 25.000 IC₅₀ Number μM μM μM μM μM μM μM μM (μM) Control 129 113 108 133 109 131 122 133 n/a* 676630 780241 117 104 92 93 76 59 58 58 n/a* 802714 100 123 98 93 75 56 44 36 6.3 803268 99 121 96 83 77 84 73 68 105.6 876031 96 99 93 73 49 22 18 15 1.0 876604 97 91 78 65 43 20 15 15 0.6 934556 97 90 77 55 42 27 20 15 0.6 *IC₅₀ value cannot be calculated

Example 13: Activity of Modified Oligonucleotides Complementary to Human LRRK2 in Transgenic Mice, Two Week Assessment

Modified oligonucleotides described above were tested in the human BAC wild type LRRK2 transgenic mouse model (B6; SJL-Tg(LRRK2)66Mjff/J; Stock No: 013725, The Jackson Laboratory) to assess activity after two weeks. Mice hemizygous for the BAC LRRK2-Wt transgene are viable and fertile. These mice express a wild-type human leucine-rich repeat kinase 2 (LRRK2) gene directed by the human LRRK2 promoter/enhancer regions on the BAC transgene (Ouyang Y et al., 2011). Mice from this model express human LRRK2 in a variety of tissues, including the spinal cord and brain.

Treatment

LRRK2 transgenic mice each received a single intracerebroventricular (ICV) dose of 300 μg of modified oligonucleotides listed in the table below. Each treatment group consisted of 4 mice. A group of 4 mice received PBS as a negative control.

RNA Analysis

After two weeks, mice were sacrificed and RNA was extracted from cortical brain tissue and spinal cord for real-time PCR analysis of measurement of RNA expression of LRRK2 using primer probe set hLRRK2 LTS35700 (described herein above in Example 11). Results are presented in the table below as percent LRRK2 RNA levels relative to relative to PBS control, normalized with cyclophilin A.

As shown in the table below, treatment with modified oligonucleotides resulted in reduction of human LRRK2 RNA in comparison to the PBS control.

TABLE 75 Reduction of human LRRK2 RNA in transgenic mice Compound LRRK2 Expression (% control) Number Cortex Spinal Cord PBS 100 100 693430 46 37 725607 24 50 725608 19 33 725609 30 37 780162 59 76 780164 27 62 780166 14 26 780189 58 49 780202 42 36 780203 65 66 780205 13 29 780219 34 43 780236 19 29 780241 23 38 780243 54 47 780254 42 41 780284 61 53 780321 39 64 780347 42 51 780549 63 53 780602 93 103 780620 47 45 780624 63 75 780649 52 48 780685 42 37 802655 30 48 802678 7 26 802685 38 32 802686 17 40 802688 18 27 802689 16 36 802731 42 44 802746 42 64 802747 56 44 802748 32 25 802845 30 26 802846 35 41 802848 68 72

TABLE 76 Reduction of human LRRK2 RNA in transgenic mice Compound LRRK2 Expression (% control) Number Cortex Spinal Cord PBS 100 100 802849 78 77 802850 73 92 802888 49 63 802911 80 92 802915 54 68 802935 69 61 802936 40 52 802937 43 40 802958 57 78 802960 54 48 802961 34 44 802962 40 51 802974 50 55 803002 30 44 803003 67 85 803004 73 86 803005 66 65 803046 95 65 803065 55 52 802959 41 62 803075 38 54 803102 89 89 803112 40 51 803122 52 71 803386 73 80 803515 81 104 803516 63 81 803517 55 67 803518 60 85 803519 70 79 803520 50 80 803571 66 71 803595 80 71 803604 65 67 803629 57 72 803682 47 46 803744 47 53 803770 73 54 803771 53 46 803773 40 50 803782 80 96

TABLE 77 Reduction of human LRRK2 RNA in transgenic mice Compound LRRK2 Expression (% control) Number Cortex Spinal Cord PBS 100 100 780160 13 15 780161 24 30 802665 17 35 802678 27 35 802690 33 40 802714 21 47 802758 23 42 802770 11 22 802781 32 49 802784 16 30 802938 21 32 802939 13 41 802963 26 51 803000 22 42 803001 36 50 803006 29 39 803268 31 52 803269 38 49 803270 24 75 803271 31 48 803272 76 75 803273 77 70 803274 50 65

TABLE 78 Reduction of human LRRK2 RNA in transgenic mice Compound LRRK2 Expression (% control) Number Cortex Spinal Cord PBS 100 100 802678 24 19 803275 52 77 872246 44 49 872247 57 63 872248 24 44 872249 61 73 872250 34 28 872251 37 51 872252 54 62 872253 29 43 872254 94 71 872256 34 44 872257 70 72 872258 55 42 872259 82 72 872260 10 30 872261 37 55 872262 50 71 872263 28 49 872264 43 67 872265 36 35 872266 92 88 872267 68 74

TABLE 79 Reduction of human LRRK2 RNA in transgenic mice Compound LRRK2 Expression (% control) Number Cortex Spinal Cord PBS 100 100 802678 9 19 802780 42 49 802847 54 64 803021 67 70 803045 36 60 803064 42 67 803123 56 76 803181 41 74 803470 34 52 803503 67 72 803665 58 84 803769 71 90 872255 23 42 872268 52 66 872269 37 54 872270 39 61 872271 94 101 872272 76 77 872273 31 38 872274 54 85 872275 84 84 872276 73 97 872277 47 67 872278 36 68 872279 39 69 874144 81 86 874145 64 67 874146 67 64 874147 78 79 874148 57 58 874149 55 69 874150 57 44 874151 102 84

TABLE 80 Reduction of human LRRK2 RNA in transgenic mice Compound LRRK2 Expression (% control) Number Cortex Spinal Cord PBS 100 100 802678 30 41 803426 70 63 872280 83 64 872281 49 64 872282 48 64 872283 61 60 872285 26 41 876019 58 72 876097 47 46 876141 47 50 876168 103 89 876180 21 27 934558 54 49 934584 45 55 934585 162 95 934586 174 102 934587 35 238 934588 30 42 934589 19 30 934590 24 50 934591 42 52 934592 38 49 934593 31 35 934594 22 45 934595 59 61 934596 n.d. n.d. 934597 48 59 934600 15 33

TABLE 81 Reduction of human LRRK2 RNA in transgenic mice Compound LRRK2 Expression (% control) Number Cortex Spinal Cord PBS 100 100 780241 55 57 802678 12 20 876185 59 56 876190 25 38 876223 46 70 876326 36 57 876345 77 79 876735 64 57 876766 67 75 876900 41 46 877068 44 52 877159 52 61 877305 52 57 877328 68 76 890207 42 60 890208 32 45 890209 40 58 934599 29 37

TABLE 82 Reduction of human LRRK2 RNA in transgenic mice Compound LRRK2 Expression (% control) Number Cortex Spinal Cord PBS 100 100 802678 15 21 803427 34 32 876028 99 61 876029 106 69 876043 55 36 876062 39 26 876074 70 35 876146 82 42 876189 54 34 876203 90 46 876221 60 31 876237 80 35 876262 58 31 876284 74 41 876287 129 57 876302 81 34 876303 76 46 876899 60 34 876960 93 41 877119 62 36 877171 67 66 877292 68 58 877326 74 58 877349 106 81 877395 69 75

TABLE 83 Reduction of human LRRK2 RNA in transgenic mice Compound LRRK2 Expression (% control) Number Cortex Spinal Cord PBS 100 100 802678 13 13 876027 166 94 876031 23 18 876042 85 60 876068 80 54 876088 48 60 876143 79 70 876186 60 45 876195 54 48 876261 32 35 876263 46 42 876282 64 45 876285 89 59 876294 37 39 876301 51 55 876328 63 53 876604 26 22 876790 87 54 877098 65 41 877176 175 74

TABLE 84 Reduction of human LRRK2 RNA in transgenic mice Compound LRRK2 Expression (% control) Number Cortex Spinal Cord PBS 100 100 802678 31 40 872284 69 57 876274 65 60 877113 76 98 877303 67 68 890206 41 77 934538 49 49 934540 80 67 934541 43 54 934542 44 63 934543 58 60 934544 46 52 934545 39 35 934546 37 44 934547 45 51 934548 37 43 934549 34 42 934552 37 35 934553 27 36 934554 23 36 934555 38 43 934556 10 17 934557 17 29 934558 46 51

TABLE 85 Reduction of human LRRK2 RNA in transgenic mice Compound LRRK2 Expression (% control) Number Cortex Spinal Cord PBS 100 100 802678 10 17 934514 17 28 934515 16 21 934516 9 26 934517 16 36 934518 25 23 934519 71 70 934520 47 27 934521 52 50 934522 45 58 934523 29 30 934524 35 38 934525 50 56 934526 41 43 934528 28 33 934529 30 33 934530 31 35 934531 33 37 934532 33 37 934533 37 32 934534 38 44 934535 80 55 934536 57 61 934537 45 45

TABLE 86 Reduction of human LRRK2 RNA in transgenic mice Compound LRRK2 Expression (% control) Number Cortex Spinal Cord PBS 100 100 802678 11 22 952334 43 27 952335 86 96 952336 34 53 952338 68 62 952340 36 36 953599 123 87 953600 105 83 953601 103 87 953602 70 89 953603 48 74 953604 36 46 953605 69 51 953606 93 74 953607 53 65 953608 41 36 953609 84 69 953610 59 61 953611 42 61 953612 47 85 953613 81 74 953614 61 62 953615 41 42 953616 79 57 953617 107 67

TABLE 87 Reduction of human LRRK2 RNA in transgenic mice Compound LRRK2 Expression (% control) Number Cortex Spinal Cord PBS 100 100 802678 16 18 952358 80 84 952359 54 66 952360 34 39 952361 51 47 952362 42 41 952363 45 42 952364 45 57 952365 39 63 952366 38 56 952367 61 50 952368 33 52 952369 56 59 952370 37 62 952371 34 56 952372 27 65 952373 43 55 952374 58 72 952375 20 42 952376 29 41 952377 20 34 952378 28 41 952379 35 49 952380 22 51 952381 22 40

Example 14: Activity of Modified Oligonucleotides Complementary to Human LRRK2 in Transgenic Mice, Eight Week Assessment

Modified oligonucleotides described above were tested in the human BAC wild type LRRK2 transgenic mouse model (described herein above) to assess activity after eight weeks. Mice hemizygous for the BAC LRRK2-Wt transgene are viable and fertile. These mice express a wild-type human leucine-rich repeat kinase 2 (LRRK2) gene directed by the human LRRK2 promoter/enhancer regions on the BAC transgene (Ouyang Y et al., 2011). Mice from this model express human LRRK2 in a variety of tissues, including the spinal cord and brain.

Treatment

LRRK2 transgenic mice each received a single ICV dose of 300 μg of modified oligonucleotides listed in the table below. Each treatment group consisted of 4 mice. A group of 4 mice received PBS as a negative control.

RNA Analysis

After eight weeks, mice were sacrificed and RNA was extracted from cortical brain tissue and spinal cord for real-time PCR analysis of measurement of RNA expression of LRRK2 using primer probe set hLRRK2 LTS35700 (described herein above in Example 11). Results are presented in the table below as percent LRRK2 RNA levels relative to relative to PBS control, normalized with cyclophilin A

As shown in the table below, treatment with modified oligonucleotides resulted in reduction of human LRRK2 RNA in comparison to the PBS control.

TABLE 88 Reduction of human LRRK2 RNA in transgenic mice Compound LRRK2 Expression in Cortex Number (% control) PBS 100 802665 44 934556 16 934517 26 802678 19 876031 33 934553 34 934554 34 780166 28 802714 27 802770 16 802938 23 803270 33 780161 39 780241 44 934557 18

TABLE 89 Reduction of human LRRK2 RNA in transgenic mice Compound LRRK2 Expression in Cortex Number (% control) PBS 100 780164 54 803000 39 803268 66 876604 78 934518 21

Example 15: Activity of Modified Oligonucleotides Complementary to Human LRRK2 in Transgenic Rats

Modified oligonucleotides described above were tested in the human BAC G2019S mutant LRRK2 transgenic rat (NTac:SD-Tg(LRRK*G2019S)571Cjli; Taconic) model to assess activity. The model was created through pronuclear injection of the entire human LRRK2 gene with the G2019S mutation into NTac:SD zygotes. Rats from this model express human LRRK2 in a variety of tissues, including the spinal cord and brain (West A B et al., J. Comp. Neurology, 2014, 522(11):2465-2480).

Treatment

LRRK2 transgenic rats each received a single ICV dose of 1,000 μg of modified oligonucleotides listed in the table below. Each treatment group consisted of 4-5 rats. A group of 4 rats received PBS as a negative control.

RNA Analysis

After two weeks, rats were sacrificed and RNA was extracted from brainstem, cortical brain tissue, spinal cord, lung and kidney for real-time PCR analysis of measurement of RNA expression of LRRK2 using primer probe set hLRRK2 LTS35700 (described herein above in Example 11). Results are presented in the table below as percent LRRK2 RNA levels relative to relative to PBS control, normalized with cyclophilin A.

As shown in the table below, treatment with modified oligonucleotides resulted in reduction of human LRRK2 RNA in comparison to the PBS control.

TABLE 90 Reduction of human LRRK2 RNA in transgenic rats LRRK2 Expression Compound (% control) Number Brainstem Cortex Spinal Cord PBS 100 100 100 780241 60 42 54 802714 43 33 53 803268 66 58 73 876031 33 9 33 876604 38 19 39 934556 31 9 35

Example 16: Potency of Modified Oligonucleotides Complementary to Human LRRK2 in Transgenic Rats

Modified oligonucleotides described above were tested in the human BAC G2019S mutant LRRK2 transgenic rat (NTac:SD-Tg(LRRK*G2019S)571Cjli) model, described herein above, to test the potency of oligonucleotides.

Treatment

LRRK2 transgenic rats each received a single intracerebroventricular (ICV) dose of 10, 30, 100, 300, 700, 1,000, or 3,000 μg of modified oligonucleotides listed in the table below. Each treatment group consisted of 5 rats. A group of 5 rats received PBS as a negative control for each dosage group.

RNA Analysis

After two weeks, rats were sacrificed and RNA was extracted from cortex for real-time PCR analysis of measurement of RNA expression of LRRK2 using primer probe set hLRRK2 LTS35700 (described herein above in Example 11). Results are presented in the table below as percent LRRK2 RNA levels relative to relative to PBS control, normalized with cyclophilin A

As shown in the table below, treatment with modified oligonucleotides resulted in reduction of human LRRK2 RNA in comparison to the PBS control. Dose response data was analyzed using GraphPad Prism 6 software (San Diego, Calif.). ED₅₀ values were calculated from log transformed dose or concentrations and individual animal LRRK2 RNA levels using the built in GraphPad formula “log(agonist) vs. response—Find ECanything”, with the following constraints: bottom>0, top=100, F=50 for ED50

TABLE 91 Dose-dependent percent reduction of human LRRK2 RNA in transgenic rats, cortex LRRK2 expression (% control) in cortex Compound 10 30 100 300 1000 3000 ED₅₀ Number μg μg μg μg μg μg (μg/g) 780241 107.4 96.4 75.9 41.9 33.1 34.9 129 876031 102.0 94.6 67.6 18.7 5.9 4.6 135 934556 105.9 94.2 56.6 17.3 7.1 3.7 111

Example 17: Tolerability of Modified Oligonucleotides Complementary to LRRK2 in Wild-Type Mice, 3 Hour FOB Assessment

Modified oligonucleotides described above were tested in wild-type female C57/B16 mice to assess the tolerability of the oligonucleotides. Wild-type female C57/B16 mice each received a single ICV dose of 700 μg of modified oligonucleotide listed in the table below. Each treatment group consisted of 4 mice. A group of 4 mice received PBS as a negative control for each experiment (identified in separate tables below). At 3 hours post-injection, mice were evaluated according to seven different criteria. The criteria are (1) the mouse was bright, alert, and responsive; (2) the mouse was standing or hunched without stimuli; (3) the mouse showed any movement without stimuli; (4) the mouse demonstrated forward movement after it was lifted; (5) the mouse demonstrated any movement after it was lifted; (6) the mouse responded to tail pinching; (7) regular breathing. For each of the 7 criteria, a mouse was given a subscore of 0 if it met the criteria and 1 if it did not (the functional observational battery score or FOB). After all 7 criteria were evaluated, the scores were summed for each mouse and averaged within each treatment group. The results are presented in the tables below.

TABLE 92 Tolerability scores in mice at 700 μg dose Compound 3 hr Number FOB PBS 0 802678 0 693430 0 725607 0 780164 0 780166 6 780205 0 780254 7 780321 0 780685 2 802685 0 802688 0 802689 0 802731 6 802746 6 802888 6 802936 4 802937 4 802959 1 802962 0 802974 0 803002 7 803075 4 803682 1

TABLE 93 Tolerability scores in mice at 700 μg dose Compound 3 hr Number FOB PBS 0 780160 0 802784 6 802939 3 803006 5 872248 7 872253 7 872260 7 872263 7 876190 2 934552 2 934553 0 934554 2 934555 2 934556 1 934557 1

TABLE 94 Tolerability scores in mice at 700 μg dose Compound 3 hr Number FOB PBS 0 872255 5 934514 4 934515 2 934516 6 934518 4 934523 7 934528 5 934529 5 934530 3 934517 4 802758 7 876180 0

TABLE 95 Tolerability scores in mice at 700 μg dose Compound 3 hr Number FOB PBS 0 780161 1 780164 5 780166 6 802665 1 802714 3 802770 4 802938 4 802963 0 803000 4 803268 4 803270 1

TABLE 96 Tolerability scores in mice at 700 μg dose Compound 3 hr Number FOB PBS 0 876031 0 876604 5

TABLE 97 Tolerability scores in mice at 700 μg dose Compound 3 hr Number FOB PBS 0 952334 2 952335 0 952336 2 952338 5 952340 3 952358 5 952359 7 952360 6 952361 4 952362 6 952363 3

TABLE 98 Tolerability scores in mice at 700 μg dose Compound 3 hr Number FOB PBS 0 952364 0 952365 0 952366 3 952367 6 952368 5 952369 7 952370 7 952371 6 952372 7 952373 7 952374 4 952375 2 952376 5 952377 6 952378 3 952379 4 952380 7 952381 6 953599 0 953600 0 953601 0 953602 0 953603 0 953604 4 953605 5 953606 6 953607 3 953608 6 953609 6 953610 3 953611 3 953612 1 953613 0 953614 2 953615 4 953616 5 953617 5

Example 18: Tolerability of Modified Oligonucleotides Complementary to Human LRRK2 in Rats, 3 Hour FOB Assessment

Modified oligonucleotides described above were tested in Sprague Dawley rats to assess the tolerability of the oligonucleotides. Sprague Dawley rats each received a single intrathecal (IT) dose of 3 mg of oligonucleotide listed in the table below. Each treatment group consisted of 3-4 rats. A group of 4 rats received PBS as a negative control for each experiment (identified in separate tables below). At 3 hours post-injection, movement of 7 different parts of the body was evaluated for each rat. The 7 body parts are (1) the rat's tail; (2) the rat's posterior posture; (3) the rat's hind limbs; (4) the rat's hind paws; (5) the rat's forepaws; (6) the rat's anterior posture; (7) the rat's head. For each of the 7 different body parts, each rat was given a sub-score of 0 if the body part was moving or 1 if the body part was not moving. For each of the 7 criteria, a rat was given a subscore of 0 if it met the criteria and 1 if it did not (the functional observational battery score or FOB). After all 7 criteria were evaluated, the scores were summed for each rat and averaged within each treatment group. The results are presented in the tables below.

TABLE 99 Tolerability scores in rats at 3 mg dose Compound 3 hr Number FOB PBS n.d. 780164 2 780166 2 780189 1 780236 4 780241 1 780243 3 780254 3 780347 0 780549 0

TABLE 100 Tolerability scores in rats at 3 mg dose Compound 3 hr Number FOB PBS 0.25 780236 5 802678 2 802688 2 802748 6 872259 3 872261 4 872269 4 872279 3

TABLE 101 Tolerability scores in rats at 3 mg dose Compound 3 hr Number FOB PBS 0 725607 1 780620 6 802888 5 802936 5 802937 5 802959 4 802961 2 802962 2 802974 3 803520 5

TABLE 102 Tolerability scores in rats at 3 mg dose Compound 3 hr Number FOB PBS 0 725609 0 780164 3 780166 6 780205 3 802689 2 802731 7 802746 5 802845 2 802846 4 876088 1

TABLE 103 Tolerability scores in rats at 3 mg dose Compound 3 hr Number FOB PBS 0 802655 5 802686 2 802688 2 803075 5 803682 1 876031 0 876261 4 876263 2 876294 2

TABLE 104 Tolerability scores in rats at 3 mg dose Compound 3 hr Number FOB PBS 0 693430 3 780219 5 780254 2 780321 3 780347 1

TABLE 105 Tolerability scoes in rats at 3 mg dose Compound 3 hr Number FOB PBS 0 780160 1 780161 2 802784 5 802938 1 802939 3 802963 2 803000 5 803006 4 803270 1 872248 3 872253 6

TABLE 106 Tolerability scores in rats at 3 mg dose Compound 3 hr Number FOB PBS 0 872260 5 872263 7 934553 0 934554 0 934555 2 934556 0 934557 0

TABLE 107 Tolerability scores in rats at 3 mg dose Compound 3 hr Number FOB PBS 0 934517 2 934523 6 934528 4 934529 1 934530 0

TABLE 108 Tolerability scores in rats at 3 mg dose Compound 3 hr Number FOB PBS 0 802678 0.5 802758 3.25 876604 5

TABLE 109 Tolerability scores in rats at 3 mg dose Compound 3 hr Number FOB PBS 0 802665 1 802714 2 802770 2 803268 3 872255 5 934516 3 934518 4

TABLE 110 Tolerability scores in rats at 3 mg dose Compound 3 hr Number FOB PBS 0 693421 2.5 690093 3.0

TABLE 111 Tolerability scores in rats at 3 mg dose Compound 3 hr Number FOB PBS 0 952334 4 952335 2 952336 3 952338 2 952358 3 952359 2

TABLE 112 Tolerability scores in rats at 3 mg dose Compound 3 hr Number FOB PBS 0 952378 5 952379 5 952380 3 952381 4 953599 1 953600 1 953601 0 953602 2 953603 0 953604 3 953605 5 953606 5

TABLE 113 Tolerability scores in rats at 3 mg dose Compound 3 hr Number FOB PBS 0 953607 3 953608 4 953609 5 953610 3 953611 4 953612 3 953613 1 953614 4 953615 1 953616 4 953617 4

TABLE 114 Tolerability scores in rats at 3 mg dose Compound 3 hr Number FOB PBS 0 952371 4 952372 4 952373 4 952374 2 952375 5 952376 4 952377 5

TABLE 115 Tolerability scores in rats at 3 mg dose Compound 3 hr Number FOB PBS 0 952340 1 952360 4 952361 3 952362 5 952363 4 952364 5 952365 2 952366 5 952367 5 952368 6 952369 4 952370 5

Example 19: Prophylactic Reduction of LRRK2 with Modified Oligonucleotides in PFF Model

Wild type mice received a single ICV injection of 700 μg of an oligonucleotide listed in the table below or PBS vehicle alone. Each treatment group consisted of eleven or twelve mice. Two weeks after oligonucleotide treatment, preformed fibrils (PFFs) of α-synuclein were injected into the striatum, resulting in formation of α-synuclein aggregates in several brain regions and motor deficits, as described (see Luk et al., Science, 2012, 338, 949-953). One control group did not receive injection of PFFs. Fifty-five days after the oligonucleotide treatment, motor function was tested in a wire hang test. The results are presented in the table below as the average length of time the mice of each treatment group remained on the wire.

One day after the wire hang test, all of the mice in each treatment group were sacrificed except for the group that received no oligonucleotide and no PFF injection; only four mice in that group were sacrificed Animals were perfused with ice-cold PBS. Ipsilateral hemispheres were fixed and processed for immunochemistry. Contralateral midbrain and striatum were dissected and frozen until RNA analysis, while entire contralateral cortex was dissected and frozen until protein analysis. LRRK2 RNA expression was analyzed by quantitative real-time PCR using the murine primer probe set RTS3043 (forward sequence GGCGAGTTATCCGCACCAT, designated herein as SEQ ID NO: 23; reverse sequence CCAAAACCAGCATGACATTCTTAA, designated herein as SEQ ID NO: 24; probe sequence TGAGAGCCATGGCCACAGCACAA, designated herein as SEQ ID NO: 25). LRRK2 RNA levels were adjusted according to total RNA content, as measured by RIBOGREEN. The results are shown in the table below as average percent inhibition relative to the wild type control group that received neither oligonucleotide treatment nor PFF injection.

LRRK2, α-synuclein, and hyperphosphorylated α-synuclein (p-α-syn) protein levels in the cortex were analyzed by western blot. Contralateral cortex tissue was first homogenized in RIPA buffer and centrifuged at 13,300×g. The supernatant was subjected to western blot for LRRK2 protein level, and β-tubulin was used as a loading control. The results indicated that LRRK2 protein levels in the cortex were significantly lower in the oligonucleotide treated animals than in the animals that did not receive oligonucleotide treatment. The pellet was resuspended in RIPA buffer, centrifuged at 100,000×g, and the resulting insoluble material was further suspended in 2% SDS buffer, followed by an additional 100,000×g spin. The resulting supernatant was analyzed by western blot for α-synuclein and p-α-syn. The results showed that PFF injection resulted in recruitment of endogenous mouse α-synuclein into insoluble aggregates, as reported in Luk et al. The aggregates were also hyperphosphorylated. Oligonucleotide treatments reduced formation of the aggregates, as evidenced by a reduction of insoluble mouse α-synuclein and p-α-syn in the western blots. p-α-syn aggregates in the substantia nigra were visualized by immunohistochemistry. The average number of aggregates observed for samples of equal size from each treatment group is shown in the table below. One-way ANOVA test of the results showed that the differences between the PBS treated and oligonucleotide treated animals were significant.

TABLE 116 Prophylactic treatment of PFF mice with LRKK2 modified oligonucleotides Time in Compound PFF wirehang test Inhibition of LRRK2 RNA (%) No. of p-α-syn Number injected (sec) Midbrain Striatum aggregates PBS No 193 0 4.0 0 PBS Yes 94 0 0 42 693421 Yes 187 52.0 49.0 12 690093 Yes 175 43.0 24.8 21

Example 20: Reduction of LRRK2 with Modified Oligonucleotide in PFF Model

The effects of oligonucleotide reduction in wild type mice after the injection of PFFs was evaluated using 690093. Mice were treated as described in Example 19 except that oligonucleotide treatment occurred two weeks after PFF injection instead of two weeks before PFF injection. Each treatment group consisted of ten animals Fifty-five days after PFF injection, the mice were assessed in a wire hang test, as described in Example 19. One day after the wire hang test, the mice were sacrificed, the midbrain, striatum, and substantia nigra were collected, and LRRK2 RNA and p-α-syn aggregates were measured, as described in Example 19. The results are shown in the table below as the averages for each treatment group. An entry of “nd” indicates that data was not collected for that treatment group. The results show that even when the modified oligonucleotide was administered after the onset of the PFF model, motor function was improved and the number of pathological aggregates was reduced.

TABLE 117 Treatment of PFF mice with LRKK2 modified oligonucleotides Time in PFF wirehang test Inhibition of LRRK2 RNA (%) No. of p-α-syn Oligo ID injected (sec) Midbrain Striatum aggregates PBS No 227 0 0 nd PBS Yes 58 0 0 49 690093 Yes 141 62.3 43.6 38

Example 21: Prophylactic Reduction of LRRK2 with Modified Oligonucleotides in PFF Model in a Long Term Study

Modified oligonucleotides were tested in a long term study to determine if long term treatment with modified oligonucleotides is protective of dopaminergic neurons. Accumulation of α-syn aggregates in the substantia nigra pars compacta compromises survival of dopaminergic neurons over time (Luk 2012, Tran 2014).

The effects of oligonucleotide reduction in wild type mice after the injection of PFFs was evaluated using 690093 or control oligonucleotide 676630, a 5-10-5 MOE gapmer with mixed phosphodiester and phosphorothioate backbone with no known target. Mice were treated as described in Example 19 except mice received a second ICV dose of 690093 at 90 days, and were sacrificed at 180 days post first ICV treatment. Each treatment group consisted of 12 animals. At sacrifice, midbrain, striatum, and substantia nigra were collected, and LRRK2 RNA and p-α-syn aggregates were measured, as described in Example 19, and dopaminergic cells were quantified by immunohistochemistry using anti-tyrosine hydroxylase (TH) antibody. The results are shown in the table below as the averages for each treatment group. The results show that in the group treated with modified oligonucleotide complementary to LRRK2, the number of pathological aggregates was reduced over a long treatment course. Additionally, quantification of TH-positive neurons showed that 690093-mediated LRRK2 suppression rescued TH-positive cells in the ipsilateral substantia nigra pars compacta as compared to control treated cells.

TABLE 118 Prophylactic treatment of PFF mice with LRKK2 modified oligonucleotides in long term study Compound PFF Inhibition of LRRK2 RNA (%) No. of p-α-syn No. of dopaminergic Number injected Midbrain Striatum aggregates cells 676630 Yes 0 0 160 5880 690093 Yes 61.7 0 48 7522

Example 22: Tolerability of Modified Oligonucleotides Complementary to Human LRRK2 in Rats, Long-Term Assessment

In separate studies run under the same conditions, modified oligonucleotides described above were tested in Sprague Dawley rats to assess the long-term tolerability of the oligonucleotides. Sprague Dawley rats each received a single intrathecal (IT) delivered dose of 3 mg of oligonucleotide or PBS. For 6 weeks beginning 1 week post-treatment, each animal was weighed and evaluated weekly by a trained observer for adverse events. Adverse events were defined as neurological dysfunction not typical in PBS-treated control animals, including, but not limited to: abnormal limb splay, abnormal gait, tremors, abnormal respiration, paralysis, and spasticity. The onset of the adverse event is defined as the week post-dosing when the dysfunction was first recorded. If no adverse event was achieved, there is no onset (−). The onset of adverse events typically correlates with a failure to thrive as defined by a lack of body weight gain/maintenance similar to PBS-treated animals Similar tolerability assessments were described in Ostergaard et al., Nucleic Acids Res. 2013 November; 41(21): 9634-9650 and Southwell et al., Mol Ther. 2014 December; 22(12): 2093-2106. As shown in the table below, 876031, 780241, 802714, 803268, 876604, and 934556 were well-tolerated in the long-term tolerability assessment.

TABLE 119 Long-term tolerability in rats at 3 mg dose Adverse event onset, Compound weeks post-treatment, Number individual animals 690093 2, 3, 4, 4 693421 4, —, —, — 876031 —, —, —, — 780241 —, —, —, — 802714 —, —, —, — 803268 —, —, —, — 876604 —, —, —, — 934556 —, —, —, — PBS —, —, —, — 

1.-74. (canceled)
 75. A modified oligonucleotide according to the following chemical structure:

or a salt thereof.
 76. The modified oligonucleotide of claim 75, which is a sodium salt or a potassium salt.
 77. A modified oligonucleotide according to the following chemical structure:


78. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation (5′ to 3′): (SEQ ID NO: 852) mCes Geo mCes Aes mCes Tds Tds Ads Ads mCds Ads Ads Tds Ads Tds mCes Aeo Tes Aes Te;

wherein, A=an adenine nucleobase, mC=a 5-methyl cytosine nucleobase, G=a guanine nucleobase, T=a thymine nucleobase, e=a 2′-MOE modified sugar, d=a 2′-deoxyribose sugar, s=a phosphorothioate internucleoside linkage, and o=a phosphodiester internucleoside linkage.
 79. A population of modified oligonucleotides of claim 75, wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotides are stereorandom.
 80. A pharmaceutical composition comprising the modified oligonucleotide of claim 75 and a pharmaceutically acceptable diluent or carrier.
 81. The pharmaceutical composition of claim 80, wherein the pharmaceutically acceptable diluent or carrier is phosphate-buffered saline or artificial cerebrospinal fluid.
 82. The pharmaceutical composition of claim 80, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline or artificial cerebrospinal fluid.
 83. A method comprising administering to a subject the pharmaceutical composition of claim
 80. 84. A population of modified oligonucleotides of claim 77, wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotides are stereorandom.
 85. A pharmaceutical composition comprising the modified oligonucleotide of claim 77 and a pharmaceutically acceptable diluent or carrier.
 86. The pharmaceutical composition of claim 85, wherein the pharmaceutically acceptable diluent or carrier is phosphate-buffered saline or artificial cerebrospinal fluid.
 87. The pharmaceutical composition of claim 85, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline or artificial cerebrospinal fluid.
 88. A method comprising administering to a subject the pharmaceutical composition of claim
 85. 89. A population of oligomeric compounds of claim 78, wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotides are stereorandom.
 90. A pharmaceutical composition comprising the oligomeric compound of claim 78 and a pharmaceutically acceptable diluent or carrier.
 91. The pharmaceutical composition of claim 90, wherein the pharmaceutically acceptable diluent or carrier is phosphate-buffered saline or artificial cerebrospinal fluid.
 92. The pharmaceutical composition of claim 90, wherein the pharmaceutical composition consists essentially of the oligomeric compound and phosphate-buffered saline or artificial cerebrospinal fluid.
 93. A method comprising administering to a subject the pharmaceutical composition of claim
 90. 94. A method of treating Parkinson's disease comprising administering to a subject having or at risk for developing Parkinson's disease a therapeutically effective amount of the pharmaceutical composition according to claim 80, thereby treating the Parkinson's disease.
 95. The method of claim 94, wherein at least one symptom or hallmark of Parkinson's disease is ameliorated.
 96. The method of claim 95, wherein the symptom or hallmark is any of ataxia, neuropathy, and aggregate formation.
 97. The method of claim 94, wherein the subject is human.
 98. A method of reducing expression of LRRK2 in a cell comprising contacting the cell with the modified oligonucleotide of claim
 75. 99. The method of claim 98, wherein the cell is a human cell. 